Association of late-onset Alzheimer's disease with genetic variation in multiple members of the
            <i>GAPD</i>
            gene family

Li, Yonghong; Nowotny, Petra; Holmans, Peter Alan; Smemo, Scott; Kauwe, John; Hinrichs, Anthony L.; Tacey, Kristina; Doil, Lisa; Luchene, Ryan van; García, Verónica; Rowland, Charles M.; Schrodi, Steven J.; Leong, Diane U.; Gogic, Goran; Chan, Joanne; Cravchik, Anibal; Ross, David A.; Lau, Kit; Kwok, Shirley; Chang, Sheng-Yung; Catanese, Joseph J.; Sninsky, John J.; White, Thomas J.; Hardy, John; Powell, John; Lovestone, Simon; Morris, John C.; Thal, Leon J.; Owen, Michael John; Williams, Julie; Goate, Alison M.; Grupe, Andrew

doi:10.1073/pnas.0403535101

Cited by 135 publications

(111 citation statements)

References 41 publications

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“…Furthermore, this marker remained significant when all Caucasian sample sets, including ours, were analyzed together. Its overall effect size is a moderate 1.20, which is similar to reports from other groups in large sample sets, including ours, for markers in DAPK1 , GALP (Grupe et al, 2007), GAPD (Li et al, 2004) and LOC439999 . While markers of such effect sizes individually are likely to have limited predictive utility, their aggregation, together with APOE, may present a useful predictor of LOAD risk.…”

Section: Discussionsupporting

confidence: 74%

SORL1 variants and risk of late-onset Alzheimer’s disease

Li¹,

Rowland²,

Catanese³

et al. 2008

Neurobiology of Disease

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A recent study reported significant association of late-onset Alzheimer's disease (LOAD) with multiple single nucleotide polymorphisms (SNPs) and haplotypes in SORL1, a neuronal sortilinrelated receptor protein known to be involved in the trafficking and processing of amyloid precursor protein.Here we attempted to validate this finding in three large, well characterized case-control series. Approximately 2,000 samples from the three series were individually genotyped for 12 SNPs, including the 10 reported significant SNPs and 2 that constitute the reported significant haplotypes. A total of 25 allelic and haplotypic association tests were performed. One SNP rs2070045 was marginally replicated in the three sample sets combined (nominal P=0.035), however this result does not remain significant when accounting for multiple comparisons. Further validation in other sample sets will be required to assess the true effects of SORL1 variants in LOAD.

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Section: Discussionsupporting

confidence: 74%

SORL1 variants and risk of late-onset Alzheimer’s disease

Li¹,

Rowland²,

Catanese³

et al. 2008

Neurobiology of Disease

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“…97,98 Moreover, recent work reported a genetic association between the GAPDH locus on chromosome 12 and an elevated risk of late-onset AD, suggesting a possible contribution of GAPDH-mediated neurotoxicity to neurodegeneration. 99 However, the sequence encoding GAPDH lacks a nuclear localization signal, and therefore the molecular pathway to cell death has remained enigmatic. Hara et al 21 recently found a regulated pathway in which NO generated in neurons S-nitrosylates the catalytic cysteine of GAPDH (Cys152 for human, and Cys150 for mouse and rat), enabling its cytotoxic activity (Figure 4).…”

Section: S-nitrosylation As a Potential Positive Regulator Of Excitotmentioning

confidence: 99%

S-Nitrosylation and uncompetitive/fast off-rate (UFO) drug therapy in neurodegenerative disorders of protein misfolding

Nakamura

Lipton

2007

Cell Death Differ

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Although activation of glutamate receptors is essential for normal brain function, excessive activity leads to a form of neurotoxicity known as excitotoxicity. Key mediators of excitotoxic damage include overactivation of N-methyl-D-aspartate (NMDA) receptors, resulting in excessive Ca 2 þ influx with production of free radicals and other injurious pathways. Overproduction of free radical nitric oxide (NO) contributes to acute and chronic neurodegenerative disorders. NO can react with cysteine thiol groups to form S-nitrosothiols and thus change protein function. S-nitrosylation can result in neuroprotective or neurodestructive consequences depending on the protein involved. Many neurodegenerative diseases manifest conformational changes in proteins that result in misfolding and aggregation. Our recent studies have linked nitrosative stress to protein misfolding and neuronal cell death. Molecular chaperones -such as protein-disulfide isomerase, glucose-regulated protein 78, and heat-shock proteins -can provide neuroprotection by facilitating proper protein folding. Here, we review the effect of S-nitrosylation on protein function under excitotoxic conditions, and present evidence that NO contributes to degenerative conditions by S-nitrosylating-specific chaperones that would otherwise prevent accumulation of misfolded proteins and neuronal cell death. In contrast, we also review therapeutics that can abrogate excitotoxic damage by preventing excessive NMDA receptor activity, in part via S-nitrosylation of this receptor to curtail excessive activity.

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“…It is possible that already identified factors are mediated through their lifelong effects on metabolism. For example, a recent study of chromosome 12 noted association with the glyceraldehyde-3-phosphate dehydrogenase (GAPDH) gene (Li et al, 2004). GAPDH has multiple biological roles, including those associated with apoptosis and energy metabolism (glycolysis).…”

Section: Amyloid Deposition Occurs In Regions Active During Young Adumentioning

confidence: 99%

Molecular, Structural, and Functional Characterization of Alzheimer's Disease: Evidence for a Relationship between Default Activity, Amyloid, and Memory

Buckner¹,

Snyder²,

Shannon³

et al. 2005

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Alzheimer's disease (AD) and antecedent factors associated with AD were explored using amyloid imaging and unbiased measures of longitudinal atrophy in combination with reanalysis of previous metabolic and functional studies. In total, data from 764 participants were compared across five in vivo imaging methods. Convergence of effects was seen in posterior cortical regions, including posterior cingulate, retrosplenial, and lateral parietal cortex. These regions were active in default states in young adults and also showed amyloid deposition in older adults with AD. At early stages of AD progression, prominent atrophy and metabolic abnormalities emerged in these posterior cortical regions; atrophy in medial temporal regions was also observed. Event-related functional magnetic resonance imaging studies further revealed that these cortical regions are active during successful memory retrieval in young adults. One possibility is that lifetime cerebral metabolism associated with regionally specific default activity predisposes cortical regions to AD-related changes, including amyloid deposition, metabolic disruption, and atrophy. These cortical regions may be part of a network with the medial temporal lobe whose disruption contributes to memory impairment.

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Association of late-onset Alzheimer's disease with genetic variation in multiple members of the GAPD gene family

Cited by 135 publications

References 41 publications

SORL1 variants and risk of late-onset Alzheimer’s disease

SORL1 variants and risk of late-onset Alzheimer’s disease

S-Nitrosylation and uncompetitive/fast off-rate (UFO) drug therapy in neurodegenerative disorders of protein misfolding

Molecular, Structural, and Functional Characterization of Alzheimer's Disease: Evidence for a Relationship between Default Activity, Amyloid, and Memory

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