Document Information

PMID 11173059  (  )
Title Pharmacogenomics of neurodegenerative diseases.
Abstract Current knowledge of sporadic degenerative disorders suggests that, despite their multifactorial etiopathogenesis, genetics plays a primary role in orchestrating the pathological events, and even dramatically changes the disease phenotype from patient to patient. Genes may act as susceptibility factors, increasing the risk of disease development, or may operate as regulatory factors, modulating the magnitude and severity of pathogenic processes or the response to drug treatment. The goal of pharmacogenomics is the application of this knowledge to elaborate more specific and effective treatments and to tailor therapies to individual patients according to their genetic profile. Here, we outline the leading theories on the etiopathogenesis of neurodegenerative diseases, including amyotrophic lateral sclerosis, Parkinson's disease, and Alzheimer disease, and we review the potential role of genetic variations, such as gene mutations and polymorphisms, in each context. We also suggest potential targets for new therapeutic approaches and variability factors for current treatments based on genotype features. Finally, we propose a few options of preventive therapeutic interventions in patients with a high genetic risk of disease. 95123 Catania, Italy.

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Targets by SciMiner Summary

HUGO ID Symbol Target Name #Occur ActualStr
620APPamyloid beta (A4) precursor protein (peptidase nexin-II, Alzheimer disease)49amyloid |
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))17superoxide dismutase |
9508PSEN1presenilin 1 (Alzheimer disease 3)15PS1 | presenilin 1 | PS-1 |
990BCL2B-cell CLL/lymphoma 213Bcl-2 | bcl 2 |
613APOEapolipoprotein E13apolipoprotein e | ApoE-containing |
9509PSEN2presenilin 2 (Alzheimer disease 4)8presenilin 2 | PS-2 | PS2 |
7808NGFnerve growth factor (beta polypeptide)8NGF-mimetic | nerve growth factor |
6692LRP1low density lipoprotein-related protein 1 (alpha-2-macroglobulin receptor)6LRP |
16SERPINA3serpin peptidase inhibitor, clade A (alpha-1 antiproteinase, antitrypsin), member 35antichymotrypsin |
2169CNTFciliary neurotrophic factor5CNTF | ciliary neurotrophic factor |
4232GDNFglial cell derived neurotrophic factor5GDNF | glial cell line derived neurotrophic factor |
6596LIFleukemia inhibitory factor (cholinergic differentiation factor)4LIF | leukemia inhibitory factor |
10417RPS27Aribosomal protein S27a4ubiquitin |
6893MAPTmicrotubule-associated protein tau4microtubule associated protein tau | tau protein |
4571GRIA1glutamate receptor, ionotropic, AMPA 14glutamate receptor |
10940SLC1A2solute carrier family 1 (glial high affinity glutamate transporter), member 24EAAT-2 |
1033BDNFbrain-derived neurotrophic factor4brain derived neurotrophic factor | BDNF |
108ACHEacetylcholinesterase (Yt blood group)3acetylcholinesterase |
3023DRD2dopamine receptor D23dopamine receptor d2 |
4638GSTP1glutathione S-transferase pi3glutathione transferase | GSTP1 |
727ARTNartemin3neurotrophic factor |
4572GRIA2glutamate receptor, ionotropic, AMPA 23GluR2 |
11049SLC6A3solute carrier family 6 (neurotransmitter transporter, dopamine), member 33dopamine transporter | DAT |
5464IGF1insulin-like growth factor 1 (somatomedin C)3insulin like growth factor 1 | IGF-1 |
9704PVALBparvalbumin3parvalbumin |
2625CYP2D6cytochrome P450, family 2, subfamily D, polypeptide 62CYP2D6 |
2228COMTcatechol-O-methyltransferase2catechol o methyltransferase |
1499CASP1caspase 1, apoptosis-related cysteine peptidase (interleukin 1, beta, convertase)2caspase 1 |
7873NOS2Anitric oxide synthase 2A (inducible, hepatocytes)2nitric oxide synthase |
6547LDLRlow density lipoprotein receptor (familial hypercholesterolemia)2low density lipoprotein receptor |
11765TGFAtransforming growth factor, alpha2transforming growth factor |
6000IL1RNinterleukin 1 receptor antagonist2interleukin 1 receptor antagonist |
6018IL6interleukin 6 (interferon, beta 2)2interleukin 6 |
1504CASP3caspase 3, apoptosis-related cysteine peptidase2caspase 3 |
12513UCHL1ubiquitin carboxyl-terminal esterase L1 (ubiquitin thiolesterase)2uch l1 | UCH-L1 |
4574GRIA4glutamate receptor, ionotrophic, AMPA 41GluR4 |
2707ACEangiotensin I converting enzyme (peptidyl-dipeptidase A) 11angiotensin converting enzyme |
11782THtyrosine hydroxylase1tyrosine hydroxylase |
18704ARD1AARD1 homolog A, N-acetyltransferase (S. cerevisiae)1n acetyltransferase |
2529CTSDcathepsin D1cathepsin d |
10939SLC1A1solute carrier family 1 (neuronal/epithelial high affinity glutamate transporter, system Xag), member 11EAAT-3 |
7739NEFLneurofilament, light polypeptide 68kDa1neurofilament light |
2595CYP1A1cytochrome P450, family 1, subfamily A, polypeptide 11CYP |
5991IL1Ainterleukin 1, alpha1interleukin 1 |
11329SSTsomatostatin1somatostatin |
6001IL2interleukin 21interleukin 2 |
1059BLMHbleomycin hydrolase1bleomycin hydrolase |
3467ESR1estrogen receptor 11estrogen receptor alpha |
1940CHMchoroideremia (Rab escort protein 1)1rep1 |
4641GSTT1glutathione S-transferase theta 11GSTT1 |
992BCL2L1BCL2-like 11bcl xl |
8023NTF3neurotrophin 31neurotrophin 3 |
10945SLC1A7solute carrier family 1 (glutamate transporter), member 71EAAT-5 |
11892TNFtumor necrosis factor (TNF superfamily, member 2)1tumor necrosis factor |
8053NUDT6nudix (nucleoside diphosphate linked moiety X)-type motif 61bFGF |
6014IL4interleukin 41interleukin 4 |
10941SLC1A3solute carrier family 1 (glial high affinity glutamate transporter), member 31EAAT-1 |
11050SLC6A4solute carrier family 6 (neurotransmitter transporter, serotonin), member 41serotonin transporter |
3676FGF2fibroblast growth factor 2 (basic)1basic fibroblast growth factor bfgf |
8024NTF4neurotrophin 41neurotrophin 4 |
2638CYP3A5cytochrome P450, family 3, subfamily A, polypeptide 51cytochrome p 450 |
950BAP1BRCA1 associated protein-1 (ubiquitin carboxy-terminal hydrolase)1ubiquitin carboxy terminal hydrolase |
8031NTRK1neurotrophic tyrosine kinase, receptor, type 11trkA |
10944SLC1A6solute carrier family 1 (high affinity aspartate/glutamate transporter), member 61EAAT-4 |

 

Targets by SciMiner Full list

HUGO ID Symbol Name ActualStr Score FlankingText
4574GRIA4glutamate receptor, ionotrophic, AMPA 4GluR41.6central nervous system and are made of four subunits GluR1_amp_#x2013 GluR4
4572GRIA2glutamate receptor, ionotropic, AMPA 2GluR21.9The presence of the GluR2 subunit makes the AMPA receptor impermeable to Ca 2 preventing
4572GRIA2glutamate receptor, ionotropic, AMPA 2GluR21.9display low levels of mRNA and protein synthesis for the GluR2 AMPA receptor subunit ( Williams et al. 1997
10941SLC1A3solute carrier family 1 (glial high affinity glutamate transporter), member 3EAAT-10.3Five human transporters have already been cloned the glial transporters EAAT-1 and EAAT-2 and the neuronal transporters EAAT-3 EAAT-4 and EAAT-5
10940SLC1A2solute carrier family 1 (glial high affinity glutamate transporter), member 2EAAT-20.3transporters have already been cloned the glial transporters EAAT-1 and EAAT-2 and the neuronal transporters EAAT-3 EAAT-4 and EAAT-5 (the the
10939SLC1A1solute carrier family 1 (neuronal/epithelial high affinity glutamate transporter, system Xag), member 1EAAT-30.3the glial transporters EAAT-1 and EAAT-2 and the neuronal transporters EAAT-3 EAAT-4 and EAAT-5 (the the latter two also function as
10944SLC1A6solute carrier family 1 (high affinity aspartate/glutamate transporter), member 6EAAT-40.3glial transporters EAAT-1 and EAAT-2 and the neuronal transporters EAAT-3 EAAT-4 and EAAT-5 (the the latter two also function as glutamate-gated
10945SLC1A7solute carrier family 1 (glutamate transporter), member 7EAAT-50.3EAAT-1 and EAAT-2 and the neuronal transporters EAAT-3 EAAT-4 and EAAT-5 (the the latter two also function as glutamate-gated chloride channels
10940SLC1A2solute carrier family 1 (glial high affinity glutamate transporter), member 2EAAT-20.3originates from a decreased expression of the glial glutamate transporter EAAT-2 ( Rothstein et al. 1995
10940SLC1A2solute carrier family 1 (glial high affinity glutamate transporter), member 2EAAT-20.3The loss of EAAT-2 is not related to genomic mutations and selective EAAT 2
10940SLC1A2solute carrier family 1 (glial high affinity glutamate transporter), member 2EAAT-20.3Alternatively EAAT-2 deficiency could derive from defective translational or post-translational mechanisms secondary
4572GRIA2glutamate receptor, ionotropic, AMPA 2GluR21.9The GluR2 subunit of the AMPA glutamate receptor and/or and or the
1033BDNFbrain-derived neurotrophic factorBDNF1.9Neurotrophic factors such as brain-derived neurotrophic factor (BDNF), BDNF ciliary neurotrophic factor (CNTF), CNTF and insulin-like growth factor-1 (IGF-1)
2169CNTFciliary neurotrophic factorCNTF2.9as brain-derived neurotrophic factor (BDNF), BDNF ciliary neurotrophic factor (CNTF), CNTF and insulin-like growth factor-1 (IGF-1) IGF-1 enhance motor neuron survival
5464IGF1insulin-like growth factor 1 (somatomedin C)IGF-11.2ciliary neurotrophic factor (CNTF), CNTF and insulin-like growth factor-1 (IGF-1) IGF-1 enhance motor neuron survival in vitro and can also exert
2169CNTFciliary neurotrophic factorCNTF2.9A mutation of the CNTF gene occurs in 2_amp_#x2013 3% of the human population leading
2169CNTFciliary neurotrophic factorCNTF2.9However the mutation of the CNTF gene may be deleterious when associated with mutations of other
6596LIFleukemia inhibitory factor (cholinergic differentiation factor)LIF1.7of other relevant genes such as leukemia inhibitory factor (LIF) LIF ( Sendtner et al. 1996
6596LIFleukemia inhibitory factor (cholinergic differentiation factor)LIF1.7LIF is another neurotrophic factor for motor neurons and a mutation
6596LIFleukemia inhibitory factor (cholinergic differentiation factor)LIF1.7neurotrophic factor for motor neurons and a mutation of the LIF gene has been detected in a small minority of amyotrophic
990BCL2B-cell CLL/lymphoma 2Bcl-21.0biochemical marker of apoptosis the altered expression of mRNA for Bcl-2 and Bax (an an anti-apoptotic and a proapoptotic gene respectively
990BCL2B-cell CLL/lymphoma 2Bcl-21.0and Bad (proapoptotic) proapoptotic genes is increased whereas that of Bcl-2 and Bcl-xL (anti-apoptotic) anti-apoptotic is decreased ( Vukosavic et al.
990BCL2B-cell CLL/lymphoma 2Bcl-21.0double transgenic mice expressing human mutant superoxide dismutase and human Bcl-2 the overexpression of Bcl-2 is associated with a significant delay
990BCL2B-cell CLL/lymphoma 2Bcl-21.0human mutant superoxide dismutase and human Bcl-2 the overexpression of Bcl-2 is associated with a significant delay in disease onset (
620APPamyloid beta (A4) precursor protein (peptidase nexin-II, Alzheimer disease)amyloid17.4the formation of Lewy bodies and its aggregation in insoluble amyloid fibrils seems to precede the accumulation of ubiquitin and neurofilaments
12513UCHL1ubiquitin carboxyl-terminal esterase L1 (ubiquitin thiolesterase)UCH-L11.3mutation in exon 4 of the ubiquitin carboxy-terminal hydrolase-L1 (UCH-L1) UCH-L1 gene has been detected on chromosome 4 indicating that abnormal
11049SLC6A3solute carrier family 6 (neurotransmitter transporter, dopamine), member 3DAT0.3under scrutiny included those for tyrosine hydroxylase dopamine transporter (DAT), DAT dopamine receptor D2 D3 D4 and D5 monoamino oxidases A
11049SLC6A3solute carrier family 6 (neurotransmitter transporter, dopamine), member 3DAT0.3A significant association between Parkinson's disease and specific polymorphisms of DAT dopamine receptor D2 and D4 monoamino oxidase-A monoamino oxidase-B and
2595CYP1A1cytochrome P450, family 1, subfamily A, polypeptide 1CYP0.6The genes of cytochrome P 450 (CYP) CYP enzymes and particularly its CYP2D6 polymorphism are the most extensively
2625CYP2D6cytochrome P450, family 2, subfamily D, polypeptide 6CYP2D60.6of cytochrome P 450 (CYP) CYP enzymes and particularly its CYP2D6 polymorphism are the most extensively investigated
2625CYP2D6cytochrome P450, family 2, subfamily D, polypeptide 6CYP2D60.6showed a significant association of the poor metabolizer genotype of CYP2D6 with an increased risk of Parkinson's disease but opposite results
4641GSTT1glutathione S-transferase theta 1GSTT10.3of exogenous toxins and the frequency of deletions of its GSTT1 locus is higher in Parkinson's disease patients
4638GSTP1glutathione S-transferase piGSTP10.3In one study the genotype distribution of GSTP1 (another another locus of glutathione transferase significantly differed between patients
4232GDNFglial cell derived neurotrophic factorGDNF1.7neurons in vivo including glial cell line-derived neurotrophic factor (GDNF), GDNF basic fibroblast growth factor (bFGF), bFGF brain-derived neurotrophic factor neurotrophin
8053NUDT6nudix (nucleoside diphosphate linked moiety X)-type motif 6bFGF1.0line-derived neurotrophic factor (GDNF), GDNF basic fibroblast growth factor (bFGF), bFGF brain-derived neurotrophic factor neurotrophin 3 neurotrophin 4/5, 4 5 ciliary
4232GDNFglial cell derived neurotrophic factorGDNF1.7Among these the most promising is the GDNF family of proteins and clinical trials with intraventricular administration of
4232GDNFglial cell derived neurotrophic factorGDNF1.7family of proteins and clinical trials with intraventricular administration of GDNF are currently underway
4232GDNFglial cell derived neurotrophic factorGDNF1.7A polymorphism in the coding region of the GDNF gene was recently detected but its possible association with Parkinson's
990BCL2B-cell CLL/lymphoma 2Bcl-21.0The apoptosis-effector molecule caspase-3 and the anti-apoptotic molecule Bcl-2 are overexpressed in the basal ganglia of patients with Parkinson's
990BCL2B-cell CLL/lymphoma 2Bcl-21.0Gene polymorphisms of apoptosis-related factors (e.g., e.g. Bax and Bcl-2 or apoptosis-effector molecules (e.g., e.g. caspase enzymes have still to
620APPamyloid beta (A4) precursor protein (peptidase nexin-II, Alzheimer disease)amyloid17.4plaques are spherical multicellular lesions containing extracellular deposits of _amp_#x3b2 -amyloid protein which is mostly in a fibrillar form ( Selkoe
6893MAPTmicrotubule-associated protein tautau1.7They are composed of hyperphosphorylated insoluble forms of microtubule-associated protein tau often conjugated with ubiquitin ( Selkoe 1999
620APPamyloid beta (A4) precursor protein (peptidase nexin-II, Alzheimer disease)amyloid17.4Role of the _amp_#x3b2 -amyloid protein
620APPamyloid beta (A4) precursor protein (peptidase nexin-II, Alzheimer disease)amyloid17.4It is a widely accepted concept that deposition of _amp_#x3b2 -amyloid protein is the key event in the pathogenesis of Alzheimer
620APPamyloid beta (A4) precursor protein (peptidase nexin-II, Alzheimer disease)amyloid17.4Alzheimer disease _amp_#x3b2 -Amyloid protein derives from a precursor named amyloid precursor protein which in neurons consists of 695-amino acid residues
620APPamyloid beta (A4) precursor protein (peptidase nexin-II, Alzheimer disease)amyloid17.4The amyloid precursor protein is a transmembrane molecule with a long extracellular
620APPamyloid beta (A4) precursor protein (peptidase nexin-II, Alzheimer disease)amyloid17.4Under physiological conditions a small amount of amyloid precursor protein undergoes secretory cleavage of a long extracellular portion
620APPamyloid beta (A4) precursor protein (peptidase nexin-II, Alzheimer disease)amyloid17.4In Alzheimer disease the processing of amyloid precursor protein is significantly altered
620APPamyloid beta (A4) precursor protein (peptidase nexin-II, Alzheimer disease)amyloid17.4Increased amounts of amyloid precursor protein are cleaved by another endoprotease named _amp_#x3b2 -secretase
620APPamyloid beta (A4) precursor protein (peptidase nexin-II, Alzheimer disease)amyloid17.4the putative intramembranous portion leads to the generation of _amp_#x3b2 -amyloid protein molecules of 40 or 42 amino acid residues _amp_#x3b2
620APPamyloid beta (A4) precursor protein (peptidase nexin-II, Alzheimer disease)amyloid17.4of disease and are accounted for by mutations of the amyloid precursor protein presenilin-1 (PS-1), PS-1 or presenilin-2 gene (PS-2) PS-2
9508PSEN1presenilin 1 (Alzheimer disease 3)PS-14.7for by mutations of the amyloid precursor protein presenilin-1 (PS-1), PS-1 or presenilin-2 gene (PS-2) PS-2 ( Rosenberg 2000
9509PSEN2presenilin 2 (Alzheimer disease 4)PS-23.4amyloid precursor protein presenilin-1 (PS-1), PS-1 or presenilin-2 gene (PS-2) PS-2 ( Rosenberg 2000
620APPamyloid beta (A4) precursor protein (peptidase nexin-II, Alzheimer disease)amyloid17.4The gene of amyloid precursor protein maps on chromosome 21q21.2 and at least 7
620APPamyloid beta (A4) precursor protein (peptidase nexin-II, Alzheimer disease)amyloid17.4_amp_#x3b3 -secretase cleavage sites altering the normal proteolysis of the amyloid precursor protein
9508PSEN1presenilin 1 (Alzheimer disease 3)PS-14.7The PS-1 gene locates on chromosome 14q24.3 and mutations in this gene
9508PSEN1presenilin 1 (Alzheimer disease 3)PS-14.7PS-1 codes for a 467-amino acid protein that is an integral
9508PSEN1presenilin 1 (Alzheimer disease 3)PS-14.7PS-1 function is not entirely known but it may be involved
9508PSEN1presenilin 1 (Alzheimer disease 3)PS-14.7More than 60 mutations of the PS-1 gene have been associated with early-onset familial Alzheimer disease and
9509PSEN2presenilin 2 (Alzheimer disease 4)PS-23.4The PS-2 gene maps on chromosome 1q31-q42 and codes for a 448-amino
9508PSEN1presenilin 1 (Alzheimer disease 3)PS-14.7for a 448-amino acid protein sharing 67% sequence homology with PS-1 protein
9509PSEN2presenilin 2 (Alzheimer disease 4)PS-23.4Two missense mutations of the PS-2 gene have been identified to date and are associated with
9508PSEN1presenilin 1 (Alzheimer disease 3)PS-14.7The high degree of sequence homology between PS-1 and PS-2 protein implies similar functions and indirect evidence suggests
9509PSEN2presenilin 2 (Alzheimer disease 4)PS-23.4The high degree of sequence homology between PS-1 and PS-2 protein implies similar functions and indirect evidence suggests that they
620APPamyloid beta (A4) precursor protein (peptidase nexin-II, Alzheimer disease)amyloid17.4they may act as or cooperate with _amp_#x3b3 -secretase in amyloid precursor protein processing ( Selkoe 1999
620APPamyloid beta (A4) precursor protein (peptidase nexin-II, Alzheimer disease)amyloid17.4a wide consensus on the hypothesis that missense mutations of amyloid precursor protein PS-1 and PS-2 genes may share a common
9508PSEN1presenilin 1 (Alzheimer disease 3)PS-14.7on the hypothesis that missense mutations of amyloid precursor protein PS-1 and PS-2 genes may share a common pathogenetic mechanism finally
9509PSEN2presenilin 2 (Alzheimer disease 4)PS-23.4hypothesis that missense mutations of amyloid precursor protein PS-1 and PS-2 genes may share a common pathogenetic mechanism finally leading to
620APPamyloid beta (A4) precursor protein (peptidase nexin-II, Alzheimer disease)amyloid17.4common pathogenetic mechanism finally leading to the accumulation of _amp_#x3b2 -amyloid protein as a byproduct of abnormal amyloid precursor protein metabolism
620APPamyloid beta (A4) precursor protein (peptidase nexin-II, Alzheimer disease)amyloid17.4accumulation of _amp_#x3b2 -amyloid protein as a byproduct of abnormal amyloid precursor protein metabolism ( Selkoe 1999
9508PSEN1presenilin 1 (Alzheimer disease 3)PS-14.7Homozygotic polymorphism at the level of intron 8 of the PS-1 gene was first reported to double the risk of late-onset
9508PSEN1presenilin 1 (Alzheimer disease 3)PS-14.7others did not and a meta-analysis concluded that such a PS-1 gene polymorphism is only slightly associated with Alzheimer disease (
9508PSEN1presenilin 1 (Alzheimer disease 3)PS-14.7Other polymorphisms in the 5_amp_#x2032 regulatory region of the PS-1 gene have also been detected and are associated with a
9508PSEN1presenilin 1 (Alzheimer disease 3)PS-14.7Alzheimer disease probably mediated by an altered expression of the PS-1 protein ( van Duijn et al. 1999
9509PSEN2presenilin 2 (Alzheimer disease 4)PS-23.4To date polymorphisms of the PS-2 gene have not been associated with Alzheimer disease
620APPamyloid beta (A4) precursor protein (peptidase nexin-II, Alzheimer disease)amyloid17.4Experimental data for transgenic mice which overexpress mutant human amyloid precursor protein and develop Alzheimer-like pathology demonstrated that immunization with
620APPamyloid beta (A4) precursor protein (peptidase nexin-II, Alzheimer disease)amyloid17.4protein and develop Alzheimer-like pathology demonstrated that immunization with _amp_#x3b2 -amyloid protein may prevent neuritic plaque formation and that peripheral administration
620APPamyloid beta (A4) precursor protein (peptidase nexin-II, Alzheimer disease)amyloid17.4prevent neuritic plaque formation and that peripheral administration of anti-_amp_#x3b2 -amyloid protein antibodies reduces neuritic plaque burden ( Schenk and Bard
620APPamyloid beta (A4) precursor protein (peptidase nexin-II, Alzheimer disease)amyloid17.4humans are currently underway and if safe immunization with _amp_#x3b2 -amyloid protein may become the first-line treatment for asymptomatic subjects with
620APPamyloid beta (A4) precursor protein (peptidase nexin-II, Alzheimer disease)amyloid17.4treatment for patients with Alzheimer disease carrying mutations of the amyloid precursor protein PS1 or PS2 gene
9508PSEN1presenilin 1 (Alzheimer disease 3)PS10.9with Alzheimer disease carrying mutations of the amyloid precursor protein PS1 or PS2 gene
9509PSEN2presenilin 2 (Alzheimer disease 4)PS21.4disease carrying mutations of the amyloid precursor protein PS1 or PS2 gene
613APOEapolipoprotein EApoE2.4the analysis of allele polymorphism of the apolipoprotein E (ApoE) ApoE gene
613APOEapolipoprotein EApoE2.4The ApoE gene maps on chromosome 19q12-q13 and contains three common coding
613APOEapolipoprotein EApoE2.4ApoE 4 is neither necessary nor sufficient to cause Alzheimer disease
613APOEapolipoprotein EApoE2.4However the increased risk of developing Alzheimer disease provided by ApoE 4 may be due to its higher affinity for _amp_#x3b2
620APPamyloid beta (A4) precursor protein (peptidase nexin-II, Alzheimer disease)amyloid17.44 may be due to its higher affinity for _amp_#x3b2 -amyloid protein compared to other alleles and to its propensity to
620APPamyloid beta (A4) precursor protein (peptidase nexin-II, Alzheimer disease)amyloid17.4to enhance the aggregation or reduce the clearance of _amp_#x3b2 -amyloid protein ( Selkoe 1999
613APOEapolipoprotein EApoE2.4at position _amp_#x2212 491 in the 5_amp_#x2032 -promoter region of ApoE has been reported to be associated with an increased risk
613APOEapolipoprotein EApoE2.4_amp_#x2212 491 polymorphism appears to be independent of that of ApoE 4 and is associated with a rise in ApoE plasma
613APOEapolipoprotein EApoE2.4of ApoE 4 and is associated with a rise in ApoE plasma levels ( Laws et al. 1999
620APPamyloid beta (A4) precursor protein (peptidase nexin-II, Alzheimer disease)amyloid17.4of them code for proteins which may participate in _amp_#x3b2 -amyloid protein processing or aggregation in neuritic plaques -1-Antichymotrypsin is a
620APPamyloid beta (A4) precursor protein (peptidase nexin-II, Alzheimer disease)amyloid17.4a protease inhibitor and an acute-phase protein also found in amyloid deposits in Alzheimer disease brains ( Abraham et al. 1988
620APPamyloid beta (A4) precursor protein (peptidase nexin-II, Alzheimer disease)amyloid17.4( Licastro et al. 2000a and contribute to enhance _amp_#x3b2 -amyloid protein aggregation ( Ma et al. 1994 or hamper its
620APPamyloid beta (A4) precursor protein (peptidase nexin-II, Alzheimer disease)amyloid17.4-2-Macroglobulin another proteinase inhibitor is detected in amyloid plaques and interacts with the lipoprotein receptor related protein (LRP),
6692LRP1low density lipoprotein-related protein 1 (alpha-2-macroglobulin receptor)LRP1.7plaques and interacts with the lipoprotein receptor related protein (LRP), LRP as do a number of other ligands including _amp_#x3b2 -amyloid
620APPamyloid beta (A4) precursor protein (peptidase nexin-II, Alzheimer disease)amyloid17.4LRP as do a number of other ligands including _amp_#x3b2 -amyloid protein amyloid precursor protein ApoE and cholesterol ( Rosenberg 2000
620APPamyloid beta (A4) precursor protein (peptidase nexin-II, Alzheimer disease)amyloid17.4do a number of other ligands including _amp_#x3b2 -amyloid protein amyloid precursor protein ApoE and cholesterol ( Rosenberg 2000 -2-Macroglobulin also
613APOEapolipoprotein EApoE2.4of other ligands including _amp_#x3b2 -amyloid protein amyloid precursor protein ApoE and cholesterol ( Rosenberg 2000 -2-Macroglobulin also binds to _amp_#x3b2
620APPamyloid beta (A4) precursor protein (peptidase nexin-II, Alzheimer disease)amyloid17.4and cholesterol ( Rosenberg 2000 -2-Macroglobulin also binds to _amp_#x3b2 -amyloid protein and such complexes may be cleared through binding to
6692LRP1low density lipoprotein-related protein 1 (alpha-2-macroglobulin receptor)LRP1.7protein and such complexes may be cleared through binding to LRP or deposition in amyloid plaques
620APPamyloid beta (A4) precursor protein (peptidase nexin-II, Alzheimer disease)amyloid17.4may be cleared through binding to LRP or deposition in amyloid plaques
620APPamyloid beta (A4) precursor protein (peptidase nexin-II, Alzheimer disease)amyloid17.4may reflect a genetically-determined defective removal of -2-macroglobulin/_amp_#x3b2;-amyloid -2-macroglobulin _amp_#x3b2 -amyloid protein complexes
6692LRP1low density lipoprotein-related protein 1 (alpha-2-macroglobulin receptor)LRP1.7LRP is a member of the low-density lipoprotein receptor superfamily and
613APOEapolipoprotein EApoE2.4and is believed to contribute to the clearance of ApoE/_amp_#x3b2;-amyloid ApoE _amp_#x3b2 -amyloid protein and -2-macroglobulin/_amp_#x3b2;-amyloid -2-macroglobulin _amp_#x3b2 -amyloid protein complexes
620APPamyloid beta (A4) precursor protein (peptidase nexin-II, Alzheimer disease)amyloid17.4believed to contribute to the clearance of ApoE/_amp_#x3b2;-amyloid ApoE _amp_#x3b2 -amyloid protein and -2-macroglobulin/_amp_#x3b2;-amyloid -2-macroglobulin _amp_#x3b2 -amyloid protein complexes ( Hyman
620APPamyloid beta (A4) precursor protein (peptidase nexin-II, Alzheimer disease)amyloid17.4of ApoE/_amp_#x3b2;-amyloid ApoE _amp_#x3b2 -amyloid protein and -2-macroglobulin/_amp_#x3b2;-amyloid -2-macroglobulin _amp_#x3b2 -amyloid protein complexes ( Hyman et al. 2000
6692LRP1low density lipoprotein-related protein 1 (alpha-2-macroglobulin receptor)LRP1.7As potential candidate gene in Alzheimer disease the LRP gene was examined for DNA variations and a tetranucleotide repeat
6692LRP1low density lipoprotein-related protein 1 (alpha-2-macroglobulin receptor)LRP1.7LRP in fact is also a receptor for cholesterol and in
620APPamyloid beta (A4) precursor protein (peptidase nexin-II, Alzheimer disease)amyloid17.4by lovastatin and methyl-_amp_#x3b2 -cyclodextrine inhibits the production of _amp_#x3b2 -amyloid protein by cultured hippocampal neurons ( Simons et al. 1998
6692LRP1low density lipoprotein-related protein 1 (alpha-2-macroglobulin receptor)LRP1.7a potential treatment for patients with Alzheimer disease carrying certain LRP genotypes ( Table 4
613APOEapolipoprotein EApoE-containing1.3density lipoprotein (VLDL) VLDL receptor functions as a receptor for ApoE-containing lipoproteins and for this reason it has been hypothesized to
6893MAPTmicrotubule-associated protein tautau1.7et al. 1999a angiotensin-converting enzyme ( Kehoe et al. 1999 tau protein ( Lilius et al. 1999 and bleomycin hydrolase (
7808NGFnerve growth factor (beta polypeptide)NGF1.2The trophic activity of nerve growth factor (NGF) NGF on cholinergic basal forebrain neurons ( Scott and Crutcher 1994
7808NGFnerve growth factor (beta polypeptide)NGF1.2NGF levels are increased in cortical areas of brains from patients
7808NGFnerve growth factor (beta polypeptide)NGF1.2patients with established Alzheimer disease whereas the number of high-affinity NGF receptors is decreased in the basal forebrain ( Hock et
8031NTRK1neurotrophic tyrosine kinase, receptor, type 1trkA1.6A reduction in the number of high-affinity trkA receptors might mediate the loss of NGF trophic activity through
7808NGFnerve growth factor (beta polypeptide)NGF1.2number of high-affinity trkA receptors might mediate the loss of NGF trophic activity through impaired retrograde axonal transport ( Mufson et
7808NGFnerve growth factor (beta polypeptide)NGF1.2Furthermore indirect but compelling evidence in favor of NGF involvement in the pathogenesis of Alzheimer disease comes from a
620APPamyloid beta (A4) precursor protein (peptidase nexin-II, Alzheimer disease)amyloid17.4a neutralizing anti-NGF recombinant antibody developed an Alzheimer-like pathology including amyloid plaques and neurofibrillary tangles ( Capsoni et al. 2000
7808NGFnerve growth factor (beta polypeptide)NGF1.2Because of the inability of NGF to cross the blood_amp_#x2013 brain barrier NGF-mimetic drugs (e.g., e.g.
7808NGFnerve growth factor (beta polypeptide)NGF-mimetic1.2the inability of NGF to cross the blood_amp_#x2013 brain barrier NGF-mimetic drugs (e.g., e.g. Neotrofin or AIT-082 have been engineered and
620APPamyloid beta (A4) precursor protein (peptidase nexin-II, Alzheimer disease)amyloid17.41999 and insulin-like growth factor-1 shows protective effects against _amp_#x3b2 -amyloid protein neurotoxicity ( Dore et al. 1999
620APPamyloid beta (A4) precursor protein (peptidase nexin-II, Alzheimer disease)amyloid17.41 exhibits opposing activities because it protects neurons against _amp_#x3b2 -amyloid protein toxicity ( Prehn et al. 1996 but enhances _amp_#x3b2
620APPamyloid beta (A4) precursor protein (peptidase nexin-II, Alzheimer disease)amyloid17.4protein toxicity ( Prehn et al. 1996 but enhances _amp_#x3b2 -amyloid protein deposition in amyloid precursor protein transgenic mice ( Wyss-Coray
620APPamyloid beta (A4) precursor protein (peptidase nexin-II, Alzheimer disease)amyloid17.4et al. 1996 but enhances _amp_#x3b2 -amyloid protein deposition in amyloid precursor protein transgenic mice ( Wyss-Coray et al. 1997
620APPamyloid beta (A4) precursor protein (peptidase nexin-II, Alzheimer disease)amyloid17.4in vitro ( Mattson et al. 1997 and reduces _amp_#x3b2 -amyloid protein production ( Xu et al. 1998
620APPamyloid beta (A4) precursor protein (peptidase nexin-II, Alzheimer disease)amyloid17.4formation of Alzheimer disease plaques by upregulating the secretion of amyloid precursor protein ( Rogers et al. 1999
620APPamyloid beta (A4) precursor protein (peptidase nexin-II, Alzheimer disease)amyloid17.4Therefore a self-amplifying circuit may occur between _amp_#x3b2 -amyloid protein and cytokines ultimately fostering the sustained formation of plaques
613APOEapolipoprotein EApoE2.4of Alzheimer disease (i.e., i.e. siblings of Alzheimer disease patients ApoE 4 carriers and bearing specific polymorphisms of cytokine genes
613APOEapolipoprotein EApoE2.4risk of Alzheimer disease ( Li and Li whereas the ApoE genotype seems to affect the response to acetylcholinesterase inhibitors (
620APPamyloid beta (A4) precursor protein (peptidase nexin-II, Alzheimer disease)amyloid17.4obscure but several data suggest that chronic deposition of _amp_#x3b2 -amyloid protein may be crucial _amp_#x3b2 -Amyloid protein up-regulates pro-apoptotic molecules
990BCL2B-cell CLL/lymphoma 2Bcl-21.0pro-apoptotic molecules such as Bax down-regulates anti-apoptotic molecules such as Bcl-2 and induces caspase enzymes ( Paradis Harada and Troy
620APPamyloid beta (A4) precursor protein (peptidase nexin-II, Alzheimer disease)amyloid17.4In turn caspases may support _amp_#x3b2 -amyloid protein synthesis by altering the normal proteolytic pathway of amyloid
620APPamyloid beta (A4) precursor protein (peptidase nexin-II, Alzheimer disease)amyloid17.4-amyloid protein synthesis by altering the normal proteolytic pathway of amyloid precursor protein ( Wellington and Hayden 2000 contributing to the
620APPamyloid beta (A4) precursor protein (peptidase nexin-II, Alzheimer disease)amyloid17.4to the accumulation and ultimately to the aggregation of _amp_#x3b2 -amyloid protein into fibrils
9508PSEN1presenilin 1 (Alzheimer disease 3)PS-14.7In addition mutated PS-1 may promote apoptosis independently of _amp_#x3b2 -amyloid protein intervention by
620APPamyloid beta (A4) precursor protein (peptidase nexin-II, Alzheimer disease)amyloid17.4In addition mutated PS-1 may promote apoptosis independently of _amp_#x3b2 -amyloid protein intervention by down-regulating neuronal survival factors ( Weihl et
4571GRIA1glutamate receptor, ionotropic, AMPA 1glutamate receptor1.0the presence of the glur2 subunit makes the ampa receptor impermeable to ca 2+ preventing a cascade of potentially toxic events triggered by the intracellular influx of ca 2+ ions through glutamate receptor ion channels day et al. 1995 .
9704PVALBparvalbuminparvalbumin1.0the second feature is the lack of the ca 2+ binding proteins calbindin d28k and parvalbumin in those motor neurons that are mostly affected by amyotrophic lateral sclerosis alexianu et al. 1994 .
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))superoxide dismutase1.0ten percent of amyotrophic lateral sclerosis cases are of familial origin and 15_amp_#x2013;20% of such families show mutations of the cu 2+ /zn 2+ superoxide dismutase gene brown 1997 .
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))superoxide dismutase1.0mutations of the superoxide dismutase gene are also found in rare cases of sporadic amyotrophic lateral sclerosis accounting for 2% of cases brown 1997 .
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))superoxide dismutase1.0however the use of transgenic mouse models expressing different human superoxide dismutase mutated proteins and superoxide dismutase gene knockout mice shows that a loss of function is not the case borchelt and reaume .
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))superoxide dismutase1.0on the contrary several lines of evidence support the hypothesis of a toxic gain of function acquired by the mutant superoxide dismutase.
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))superoxide dismutase1.0mutations may induce structural changes of the superoxide dismutase causing polypeptide unfolding around the active site with abnormal entry of reactive species i.e. c oono and subsequent nitration of tyrosine residues crow et al. 1997 .
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))superoxide dismutase1.0alternatively increased accessibility to the cu 2+ active site of the mutant superoxide dismutase may lead to the use of additional substrates such as hydrogen peroxide and peroxynitrite with the production of highly toxic hydroxyl radicals wiedau pazos et al. 1996 .
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))superoxide dismutase1.0the oxidative stress hypothesis may warrant the search for superoxide dismutase gene mutations in patients with amyotrophic lateral sclerosis regardless of whether it is the sporadic or familial form before treatment is started.
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))superoxide dismutase1.0if abnormal superoxide dismutase activity is demonstrated potential therapeutic approaches may include administration of free radical scavenging drugs or cu 2+ chelators table 1 .
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))superoxide dismutase1.0inhibition of the cu 2+ chaperone for superoxide dismutase a specific protein involved in cu 2+ acquisition by superoxide dismutase could also prevent cu 2+ mediated toxicity.
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))superoxide dismutase1.0gene therapy represents a potential future perspective for superoxide dismutase related amyotrophic lateral sclerosis forms although the simple transfection of the wild type superoxide dismutase gene may not be sufficient to cure the disease as inactivation of mutated superoxide dismutase might be needed.
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))superoxide dismutase1.0 gene may not be sufficient to cure the disease as inactivation of mutated superoxide dismutase might be needed.
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))superoxide dismutase1.0such neurofilaments are often phosphorylated and may also be found within intracellular inclusions in motor neurons of patients with superoxide dismutase related familial amyotrophic lateral sclerosis manetto and murayama .
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))superoxide dismutase1.0neurofilaments may also represent a favorite target for the mutated superoxide dismutase as their light subunits are more susceptible to superoxide dismutase catalyzed nitration than are other proteins of the central nervous system crow et al. 1997 .
7739NEFLneurofilament, light polypeptide 68kDaneurofilament light1.0moreover transgenic mice expressing increased quantities of neurofilament light or heavy subunits develop motor neuron pathology cote and xu .
4571GRIA1glutamate receptor, ionotropic, AMPA 1glutamate receptor1.0in the next few years research will probably discover new and more efficacious glutamate receptor antagonists or release inhibitors and we might witness the deployment of gene therapy approaches to reduce motor neuron vulnerability to glutamatergic excitoxicity in amyotrophic lateral sclerosis pa
9704PVALBparvalbuminparvalbumin1.0the glur2 subunit of the ampa glutamate receptor and/or the calcium binding proteins calbindin d28k and parvalbumin seem to be reasonable targets: increasing the expression of such genes may improve the survival of residual motor neurons in amyotrophic lateral sclerosis.
4571GRIA1glutamate receptor, ionotropic, AMPA 1glutamate receptor1.0the glur2 subunit of the ampa glutamate receptor and/or the calcium binding proteins calbindin d28k and parvalbumin seem to be reasonable targets: increasing the expression of such genes may improve the survival of residual motor neurons in amyotro
9704PVALBparvalbuminparvalbumin1.0in addition abnormal ca 2+ entry into motor neurons may be aggravated by their constitutive lack of ca 2+ binding proteins i.e. calbinding d28k and parvalbumin .
2169CNTFciliary neurotrophic factorciliary neurotrophic factor1.0neurotrophic factors such as brain derived neurotrophic factor bdnf ciliary neurotrophic factor cntf and insulin like growth factor 1 igf 1 enhance motor neuron survival in vitro and can also exert beneficial effects in mouse models of amyotrophic lateral sclerosis reviewed in yuen and mobley 1
5464IGF1insulin-like growth factor 1 (somatomedin C)insulin like growth factor 11.0neurotrophic factors such as brain derived neurotrophic factor bdnf ciliary neurotrophic factor cntf and insulin like growth factor 1 igf 1 enhance motor neuron survival in vitro and can also exert beneficial effects in mouse models of amyotrophic lateral sclerosis reviewed in yuen and mobley 1996 .
1033BDNFbrain-derived neurotrophic factorbrain derived neurotrophic factor1.0neurotrophic factors such as brain derived neurotrophic factor bdnf ciliary neurotrophic factor cntf and insulin like growth factor 1 igf 1 enhance motor neuron survival in vitro and can also exert beneficial effects in mouse models of amyotrophic lateral sclero
6596LIFleukemia inhibitory factor (cholinergic differentiation factor)leukemia inhibitory factor1.0however the mutation of the cntf gene may be deleterious when associated with mutations of other relevant genes such as leukemia inhibitory factor lif sendtner et al. 1996 .
727ARTNarteminneurotrophic factor1.0lif is another neurotrophic factor for motor neurons and a mutation of the lif gene has been detected in a small minority of amyotrophic lateral sclerosis patients giess et al. 2000 .
990BCL2B-cell CLL/lymphoma 2bcl 21.0these findings include evidence of dna fragmentation a biochemical marker of apoptosis the altered expression of mrna for bcl 2 and bax an anti apoptotic and a proapoptotic gene respectively and the demonstration of caspase 1 and caspase 3 activation which are specific intracellular proteases responsible for the execution of
1499CASP1caspase 1, apoptosis-related cysteine peptidase (interleukin 1, beta, convertase)caspase 11.0nclude evidence of dna fragmentation a biochemical marker of apoptosis the altered expression of mrna for bcl 2 and bax an anti apoptotic and a proapoptotic gene respectively and the demonstration of caspase 1 and caspase 3 activation which are specific intracellular proteases responsible for the execution of the cell death program yoshiyama ; martin and li .
1504CASP3caspase 3, apoptosis-related cysteine peptidasecaspase 31.0e of dna fragmentation a biochemical marker of apoptosis the altered expression of mrna for bcl 2 and bax an anti apoptotic and a proapoptotic gene respectively and the demonstration of caspase 1 and caspase 3 activation which are specific intracellular proteases responsible for the execution of the cell death program yoshiyama ; martin and li .
990BCL2B-cell CLL/lymphoma 2bcl 21.0in spinal cord of human mutant superoxide dismutase transgenic mice the expression of bax and bad proapoptotic genes is increased whereas that of bcl 2 and bcl xl anti apoptotic is decreased vukosavic et al. 1999 .
992BCL2L1BCL2-like 1bcl xl1.0in spinal cord of human mutant superoxide dismutase transgenic mice the expression of bax and bad proapoptotic genes is increased whereas that of bcl 2 and bcl xl anti apoptotic is decreased vukosavic et al. 1999 .
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))superoxide dismutase1.0in spinal cord of human mutant superoxide dismutase transgenic mice the expression of bax and bad proapoptotic genes is increased whereas that of bcl 2 and bcl xl anti apoptotic is decreased vukosavic et al. 1999 .
990BCL2B-cell CLL/lymphoma 2bcl 21.0in double transgenic mice expressing human mutant superoxide dismutase and human bcl 2 the overexpression of bcl 2 is associated with a significant delay in disease onset kostic et al. 1997 .
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))superoxide dismutase1.0in double transgenic mice expressing human mutant superoxide dismutase and human bcl 2 the overexpression of bcl 2 is associated with a significant delay in disease onset kostic et al. 1997 .
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))superoxide dismutase1.0furthermore the administration of the caspase inhibitor z val ala asp fluoromethylketone zvad fmk to mutant superoxide dismutase transgenic mice reduces disease progression and increases survival li et al. 2000 .
1499CASP1caspase 1, apoptosis-related cysteine peptidase (interleukin 1, beta, convertase)caspase 11.0interestingly caspase 1 formerly called interleukin 1_amp_#x3b2; converting enzyme is responsible for the cleavage of mature interleukin 1_amp_#x3b2; from its precursor and interleukin 1_amp_#x3b2; levels are increased in a
10417RPS27Aribosomal protein S27aubiquitin1.0these inclusions appear concentric with a dense core surrounded by a filamentous halo and contain neurofilament proteins such as tubulin and ubiquitin forno 1996 .
10417RPS27Aribosomal protein S27aubiquitin1.0recent studies though established a primary role for synuclein in the formation of lewy bodies and its aggregation in insoluble amyloid fibrils seems to precede the accumulation of ubiquitin and neurofilaments goedert et al. 1998 .
1940CHMchoroideremia (Rab escort protein 1)rep11.0studies focused on the synuclein gene in sporadic parkinson's disease have revealed that allele polymorphism of the promoter sequence nac rep1 is significantly associated with an increased risk of disease development especially in combination with the apolipoprotein apo allele 4 kruger et al. 1999 .
10417RPS27Aribosomal protein S27aubiquitin1.0in a small german pedigree a point mutation in exon 4 of the ubiquitin carboxy terminal hydrolase l1 uch l1 gene has been detected on chromosome 4 indicating that abnormal proteolytic mechanisms may favor aggregation and ubiquitination of proteins like synuclein leroy e
950BAP1BRCA1 associated protein-1 (ubiquitin carboxy-terminal hydrolase)ubiquitin carboxy terminal hydrolase1.0in a small german pedigree a point mutation in exon 4 of the ubiquitin carboxy terminal hydrolase l1 uch l1 gene has been detected on chromosome 4 indicating that abnormal proteolytic mechanisms may favor aggregation and ubiquitination of proteins like synuclein leroy et al. 1998 .
12513UCHL1ubiquitin carboxyl-terminal esterase L1 (ubiquitin thiolesterase)uch l11.0in a small german pedigree a point mutation in exon 4 of the ubiquitin carboxy terminal hydrolase l1 uch l1 gene has been detected on chromosome 4 indicating that abnormal proteolytic mechanisms may favor aggregation and ubiquitination of proteins like synuclein leroy et al. 1998 .
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))superoxide dismutase1.0free radical mediated cellular damage is commonly prevented by the scavenging activity of superoxide dismutase which converts superoxide ions to hydrogen peroxide and glutathione peroxidase which converts hydrogen peroxide to water and oxidated glutathione disulfide .
7873NOS2Anitric oxide synthase 2A (inducible, hepatocytes)nitric oxide synthase1.0 ion pump activity and therefore atp expenditure in dopaminergic cells with a mitochondrial dysfunction due to a defective complex i. the concomitant rise in intracellular ca 2+ levels would activate nitric oxide synthase with the subsequent generation of toxic free radicals such as peroxynitrites.
4571GRIA1glutamate receptor, ionotropic, AMPA 1glutamate receptor1.0this potential mechanism of damage to nigral neurons has already prompted a trial with remacemide a glutamate receptor antagonist in parkinson's disease parkinson study group 2000 .
11782THtyrosine hydroxylasetyrosine hydroxylase1.0the genes under scrutiny included those for tyrosine hydroxylase dopamine transporter dat dopamine receptor d2 d3 d4 and d5 monoamino oxidases a and b and catechol o methyltransferase.
3023DRD2dopamine receptor D2dopamine receptor d21.0the genes under scrutiny included those for tyrosine hydroxylase dopamine transporter dat dopamine receptor d2 d3 d4 and d5 monoamino oxidases a and b and catechol o methyltransferase.
11049SLC6A3solute carrier family 6 (neurotransmitter transporter, dopamine), member 3dopamine transporter1.0the genes under scrutiny included those for tyrosine hydroxylase dopamine transporter dat dopamine receptor d2 d3 d4 and d5 monoamino oxidases a and b and catechol o methyltransferase.
2228COMTcatechol-O-methyltransferasecatechol o methyltransferase1.0the genes under scrutiny included those for tyrosine hydroxylase dopamine transporter dat dopamine receptor d2 d3 d4 and d5 monoamino oxidases a and b and catechol o methyltransferase.
3023DRD2dopamine receptor D2dopamine receptor d21.0a significant association between parkinson's disease and specific polymorphisms of dat dopamine receptor d2 and d4 monoamino oxidase a monoamino oxidase b and catechol o methyltransferase genes was demonstrated in some studies but not in others see tan et al. 2000 for review .
2228COMTcatechol-O-methyltransferasecatechol o methyltransferase1.0a significant association between parkinson's disease and specific polymorphisms of dat dopamine receptor d2 and d4 monoamino oxidase a monoamino oxidase b and catechol o methyltransferase genes was demonstrated in some studies but not in others see tan et al. 2000 for review .
3023DRD2dopamine receptor D2dopamine receptor d21.0stingly a study has recently reported a reduced risk of developing levodopa induced dyskinesias in patients with parkinson's disease carrying the 13 or the 14 short tandem repeat polymorphisms of the dopamine receptor d2 gene oliveri et al. 1999 .
2638CYP3A5cytochrome P450, family 3, subfamily A, polypeptide 5cytochrome p 4501.0the genes of cytochrome p 450 cyp enzymes and particularly its cyp2d6 polymorphism are the most extensively investigated.
18704ARD1AARD1 homolog A, N-acetyltransferase (S. cerevisiae)n acetyltransferase1.0in a series of investigations polymorphisms of the n acetyltransferase gene resulting in a slow acetylator phenotype were found to be significantly associated with parkinson's disease.
4638GSTP1glutathione S-transferase piglutathione transferase1.0glutathione transferase is involved in the detoxification of exogenous toxins and the frequency of deletions of its gstt1 locus is higher in parkinson's disease patients.
4638GSTP1glutathione S-transferase piglutathione transferase1.0in one study the genotype distribution of gstp1 another locus of glutathione transferase significantly differed between patients and controls that had been exposed to pesticides menegon et al. 1998 .
8023NTF3neurotrophin 3neurotrophin 31.0rophic factors show protective effects on dopaminergic neurons in vivo including glial cell line derived neurotrophic factor gdnf basic fibroblast growth factor bfgf brain derived neurotrophic factor neurotrophin 3 neurotrophin 4/5 ciliary neurotrophic factor and transforming growth factor tgf _amp_#x3b2; dunnett and bj_amp_#xf6;rklund 1999 .
8024NTF4neurotrophin 4neurotrophin 41.0show protective effects on dopaminergic neurons in vivo including glial cell line derived neurotrophic factor gdnf basic fibroblast growth factor bfgf brain derived neurotrophic factor neurotrophin 3 neurotrophin 4/5 ciliary neurotrophic factor and transforming growth factor tgf _amp_#x3b2; dunnett and bj_amp_#xf6;rklund 1999 .
2169CNTFciliary neurotrophic factorciliary neurotrophic factor1.0ffects on dopaminergic neurons in vivo including glial cell line derived neurotrophic factor gdnf basic fibroblast growth factor bfgf brain derived neurotrophic factor neurotrophin 3 neurotrophin 4/5 ciliary neurotrophic factor and transforming growth factor tgf _amp_#x3b2; dunnett and bj_amp_#xf6;rklund 1999 .
3676FGF2fibroblast growth factor 2 (basic)basic fibroblast growth factor bfgf1.0a number of neurotrophic factors show protective effects on dopaminergic neurons in vivo including glial cell line derived neurotrophic factor gdnf basic fibroblast growth factor bfgf brain derived neurotrophic factor neurotrophin 3 neurotrophin 4/5 ciliary neurotrophic factor and transforming growth factor tgf _amp_#x3b2; dunnett and bj_amp_#xf6;rklund 1999 .
11765TGFAtransforming growth factor, alphatransforming growth factor1.0n vivo including glial cell line derived neurotrophic factor gdnf basic fibroblast growth factor bfgf brain derived neurotrophic factor neurotrophin 3 neurotrophin 4/5 ciliary neurotrophic factor and transforming growth factor tgf _amp_#x3b2; dunnett and bj_amp_#xf6;rklund 1999 .
4232GDNFglial cell derived neurotrophic factorglial cell line derived neurotrophic factor1.0a number of neurotrophic factors show protective effects on dopaminergic neurons in vivo including glial cell line derived neurotrophic factor gdnf basic fibroblast growth factor bfgf brain derived neurotrophic factor neurotrophin 3 neurotrophin 4/5 ciliary neurotrophic factor and transforming growth factor tgf _amp_#x3b2; dunnett and bj_am
1033BDNFbrain-derived neurotrophic factorbrain derived neurotrophic factor1.0a number of neurotrophic factors show protective effects on dopaminergic neurons in vivo including glial cell line derived neurotrophic factor gdnf basic fibroblast growth factor bfgf brain derived neurotrophic factor neurotrophin 3 neurotrophin 4/5 ciliary neurotrophic factor and transforming growth factor tgf _amp_#x3b2; dunnett and bj_amp_#xf6;rklund 1999 .
11892TNFtumor necrosis factor (TNF superfamily, member 2)tumor necrosis factor1.0activated microglia and astrocytosis as well as increased amounts of inflammatory cytokines such as interleukin 1_amp_#x3b2; interferon _amp_#x3b3; and tumor necrosis factor are detected in the parkinsonian substantia nigra marsden and hirsch .
6001IL2interleukin 2interleukin 21.0furthermore interleukin 2 interleukin 4 and interleukin 6 levels are elevated in the ventricular cerebrospinal fluid and in the caudate nucleus and putamen of patients with parkinson's disease hirsch 2000 .
6014IL4interleukin 4interleukin 41.0furthermore interleukin 2 interleukin 4 and interleukin 6 levels are elevated in the ventricular cerebrospinal fluid and in the caudate nucleus and putamen of patients with parkinson's disease hirsch 2000 .
6018IL6interleukin 6 (interferon, beta 2)interleukin 61.0furthermore interleukin 2 interleukin 4 and interleukin 6 levels are elevated in the ventricular cerebrospinal fluid and in the caudate nucleus and putamen of patients with parkinson's disease hirsch 2000 .
990BCL2B-cell CLL/lymphoma 2bcl 21.0the apoptosis effector molecule caspase 3 and the anti apoptotic molecule bcl 2 are overexpressed in the basal ganglia of patients with parkinson's disease confirming that apoptosis is a relevant mechanism of neural death in this paradigm marshall and hartmann .
1504CASP3caspase 3, apoptosis-related cysteine peptidasecaspase 31.0the apoptosis effector molecule caspase 3 and the anti apoptotic molecule bcl 2 are overexpressed in the basal ganglia of patients with parkinson's disease confirming that apoptosis is a relevant mechanism of neural death in this paradigm ma
990BCL2B-cell CLL/lymphoma 2bcl 21.0gene polymorphisms of apoptosis related factors e.g. bax and bcl 2 or apoptosis effector molecules e.g. caspase enzymes have still to be investigated in parkinson's disease although they may play a role in modulating the susceptibility of nigral neurons to set off a
10417RPS27Aribosomal protein S27aubiquitin1.0they are composed of hyperphosphorylated insoluble forms of microtubule associated protein tau often conjugated with ubiquitin selkoe 1999 .
6893MAPTmicrotubule-associated protein taumicrotubule associated protein tau1.0they are composed of hyperphosphorylated insoluble forms of microtubule associated protein tau often conjugated with ubiquitin selkoe 1999 .
9508PSEN1presenilin 1 (Alzheimer disease 3)presenilin 11.0about half of the autosomal dominant inherited forms of alzheimer disease feature an early onset of disease and are accounted for by mutations of the amyloid precursor protein presenilin 1 ps 1 or presenilin 2 gene ps 2 rosenberg 2000 .
9509PSEN2presenilin 2 (Alzheimer disease 4)presenilin 21.0about half of the autosomal dominant inherited forms of alzheimer disease feature an early onset of disease and are accounted for by mutations of the amyloid precursor protein presenilin 1 ps 1 or presenilin 2 gene ps 2 rosenberg 2000 .
613APOEapolipoprotein Eapolipoprotein e1.0at present the most important genetic information in patients with late onset alzheimer disease comes from the analysis of allele polymorphism of the apolipoprotein e apoe gene.
16SERPINA3serpin peptidase inhibitor, clade A (alpha-1 antiproteinase, antitrypsin), member 3antichymotrypsin1.0some of them code for proteins which may participate in _amp_#x3b2; amyloid protein processing or aggregation in neuritic plaques. 1 antichymotrypsin is a protease inhibitor and an acute phase protein also found in amyloid deposits in alzheimer disease brains abraham et al. 1988 .
16SERPINA3serpin peptidase inhibitor, clade A (alpha-1 antiproteinase, antitrypsin), member 3antichymotrypsin1.0a polymorphism in the region coding for the signal peptide of the 1 antichymotrypsin gene was originally reported to confer a higher risk of alzheimer disease kamboh et al. 1995 .
16SERPINA3serpin peptidase inhibitor, clade A (alpha-1 antiproteinase, antitrypsin), member 3antichymotrypsin1.0recent data suggest that specific polymorphism of the 1 antichymotrypsin gene may rather increase the risk for early onset alzheimer disease and that this effect is enhanced by a concomitant polymorphism of the interleukin1_amp_#x3b2; gene.
16SERPINA3serpin peptidase inhibitor, clade A (alpha-1 antiproteinase, antitrypsin), member 3antichymotrypsin1.0 licastro and licastro . 1 antichymotrypsin release in the brains of alzheimer disease patients may be secondary to local inflammatory reactions licastro et al. 2000a and contribute to enhance _amp_#x3b2; amyloid protein aggregation ma et al.
6000IL1RNinterleukin 1 receptor antagonistinterleukin 1 receptor antagonist1.0therefore polymorphism analysis of the 1 antichymotrypsin gene especially in conjunction with that of the interleukin 1 gene may provide further indications for the use of anti inflammatory drugs or interleukin 1 receptor antagonist in alzheimer disease table 4 .
16SERPINA3serpin peptidase inhibitor, clade A (alpha-1 antiproteinase, antitrypsin), member 3antichymotrypsin1.0therefore polymorphism analysis of the 1 antichymotrypsin gene especially in conjunction with that of the interleukin 1 gene may provide further indications for the use of anti inflammatory drugs or interleukin 1 receptor antagonist in alzheimer disease tab
6547LDLRlow density lipoprotein receptor (familial hypercholesterolemia)low density lipoprotein receptor1.0lrp is a member of the low density lipoprotein receptor superfamily and is believed to contribute to the clearance of apoe/_amp_#x3b2; amyloid protein and 2 macroglobulin/_amp_#x3b2; amyloid protein complexes hyman et al. 2000 .
6547LDLRlow density lipoprotein receptor (familial hypercholesterolemia)low density lipoprotein receptor1.0another member of the low density lipoprotein receptor superfamily the very low density lipoprotein vldl receptor functions as a receptor for apoe containing lipoproteins and for this reason it has been hypothesized to be a potential risk factor for alzh
2529CTSDcathepsin Dcathepsin d1.0other gene polymorphisms have been reported to add to the risk of developing alzheimer disease including cathepsin d papassotiropoulos et al. 1999a angiotensin converting enzyme kehoe et al. 1999 tau protein lilius et al. 1999 and bleomycin hydrolase montoya et al. 1998 .
1059BLMHbleomycin hydrolasebleomycin hydrolase1.0een reported to add to the risk of developing alzheimer disease including cathepsin d papassotiropoulos et al. 1999a angiotensin converting enzyme kehoe et al. 1999 tau protein lilius et al. 1999 and bleomycin hydrolase montoya et al. 1998 .
6893MAPTmicrotubule-associated protein tautau protein1.0other gene polymorphisms have been reported to add to the risk of developing alzheimer disease including cathepsin d papassotiropoulos et al. 1999a angiotensin converting enzyme kehoe et al. 1999 tau protein lilius et al. 1999 and bleomycin hydrolase montoya et al. 1998 .
2707ACEangiotensin I converting enzyme (peptidyl-dipeptidase A) 1angiotensin converting enzyme1.0other gene polymorphisms have been reported to add to the risk of developing alzheimer disease including cathepsin d papassotiropoulos et al. 1999a angiotensin converting enzyme kehoe et al. 1999 tau protein lilius et al. 1999 and bleomycin hydrolase montoya et al. 1998 .
7808NGFnerve growth factor (beta polypeptide)nerve growth factor1.0the trophic activity of nerve growth factor ngf on cholinergic basal forebrain neurons scott and crutcher 1994 the main population of nerve cells that degenerate in alzheimer disease indicated that neurotrophic factors could play a primary rol
727ARTNarteminneurotrophic factor1.0brain derived neurotrophic factor levels are decreased in alzheimer disease hippocampi ferrer et al. 1999 and insulin like growth factor 1 shows protective effects against _amp_#x3b2; amyloid protein neurotoxicity dore et al. 1999 .
5464IGF1insulin-like growth factor 1 (somatomedin C)insulin like growth factor 11.0brain derived neurotrophic factor levels are decreased in alzheimer disease hippocampi ferrer et al. 1999 and insulin like growth factor 1 shows protective effects against _amp_#x3b2; amyloid protein neurotoxicity dore et al. 1999 .
1033BDNFbrain-derived neurotrophic factorbrain derived neurotrophic factor1.0brain derived neurotrophic factor levels are decreased in alzheimer disease hippocampi ferrer et al. 1999 and insulin like growth factor 1 shows protective effects against _amp_#x3b2; amyloid protein neurotoxicity dore et al. 1999 .
11765TGFAtransforming growth factor, alphatransforming growth factor1.0transforming growth factor _amp_#x3b2;1 exhibits opposing activities because it protects neurons against _amp_#x3b2; amyloid protein toxicity prehn et al. 1996 but enhances _amp_#x3b2; amyloid protein deposition in amyloid pre
727ARTNarteminneurotrophic factor1.0so far dna variations of neurotrophic factor or neurotrophic factor receptor genes have been only marginally investigated in patients with alzheimer disease but more knowledge of such variations may have a tremendous impact on future therapeutic strategies table 4 .
3467ESR1estrogen receptor 1estrogen receptor alpha1.0moreover a polymorphism of the estrogen receptor alpha gene is associated with a higher risk of developing late onset sporadic alzheimer disease brandi et al. 1999 .
7873NOS2Anitric oxide synthase 2A (inducible, hepatocytes)nitric oxide synthase1.0alzheimer disease since it induces microglia activation and the production of several inflammatory cytokines and chemokines including interleukin 1_amp_#x3b2; with subsequent stimulation of inducible nitric oxide synthase and further oxidative damage to neurons berger ; yates and akama .
5991IL1Ainterleukin 1, alphainterleukin 11.0interestingly interleukin 1 may contribute to the formation of alzheimer disease plaques by upregulating the secretion of amyloid precursor protein rogers et al. 1999 .
6018IL6interleukin 6 (interferon, beta 2)interleukin 61.0in contrast the c allele of a variable number of tandem repeat polymorphism in the 3' flanking region of the interleukin 6 gene is associated with a delayed onset and a lower risk of alzheimer disease papassotiropoulos et al. 1999b .
6000IL1RNinterleukin 1 receptor antagonistinterleukin 1 receptor antagonist1.0therapeutic trials involving the use of anti inflammatory drugs or interleukin 1 antagonists e.g. interleukin 1 receptor antagonist inhibitors of interleukin 1 converting enzyme are now being planned: results are eagerly awaited as they may lead to substantial changes in treatment protocols for alzheimer disease table 4 .
108ACHEacetylcholinesterase (Yt blood group)acetylcholinesterase1.0the beneficial effects of acetylcholinesterase inhibitors also provide further clues about the role of defective cholinergic transmission in the development of cognitive and behavioral symptoms in alzheimer disease emilien et al. 2000 .
11329SSTsomatostatinsomatostatin1.0neuropeptides such as corticotrophin releasing factor and somatostatin are also lost in alzheimer disease probably reflecting damage to cortical interneurons nemeroff et al. 1991 .
11050SLC6A4solute carrier family 6 (neurotransmitter transporter, serotonin), member 4serotonin transporter1.0to date only a low transcriptional activity allele of the serotonin transporter gene has been found to confer a higher risk of alzheimer disease li and li whereas the apoe genotype seems to affect the response to acetylcholinesterase inhibitors richard et al. 1997 .
108ACHEacetylcholinesterase (Yt blood group)acetylcholinesterase1.0a low transcriptional activity allele of the serotonin transporter gene has been found to confer a higher risk of alzheimer disease li and li whereas the apoe genotype seems to affect the response to acetylcholinesterase inhibitors richard et al. 1997 .
108ACHEacetylcholinesterase (Yt blood group)acetylcholinesterase1.0genotypes of acetylcholine related enzymes receptors and transporters are currently been analyzed to clarify whether acetylcholinesterase inhibitors have a better therapeutic effect in selected cohorts of patients than in the whole alzheimer disease population table 4 .
990BCL2B-cell CLL/lymphoma 2bcl 21.0est that chronic deposition of _amp_#x3b2; amyloid protein may be crucial. _amp_#x3b2; amyloid protein up regulates pro apoptotic molecules such as bax down regulates anti apoptotic molecules such as bcl 2 and induces caspase enzymes paradis ; harada and troy .