Genetic association study on in and around the APOE in late-onset Alzheimer disease in Japanese

Takei, Norihiro; Miyashita, Akinori; Tsukie, Tamao; Arai, Hiroyuki; Asada, Takashi; Imagawa, Masaki; Shoji, Mikio; Higuchi, Susumu; Urakami, Katsuya; Kimura, Hideo; Kakita, Akiyoshi; Takahashi, Hitoshi; Tsuji, Shoji; Kanazawa, Ichiro; Ihara, Yasuo; Okada, Shoji; Kuwano, Ryozo

doi:10.1016/j.ygeno.2009.01.003

Cited by 135 publications

(95 citation statements)

References 35 publications

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“…Included here are mutations in TIM8a, a translocase of the mitochondrial inner membrane, which are causative for deafness and dystonia in Mohr-Tranebjaerg syndrome (50). Furthermore, single nucleotide polymorphisms in the TOM40 gene have been associated with an increased risk for late-onset Alzheimer's disease (51,52), and one previous study has suggested that amyloid-β associates directly with TOM40 (53). Thus, our data add to a growing body of evidence that deficits in mitochondrial protein import pathways may contribute to neurodegenerative diseases.…”

Section: Discussionmentioning

confidence: 99%

ALS-linked mutant superoxide dismutase 1 (SOD1) alters mitochondrial protein composition and decreases protein import

Velde²,

Israelson³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

151

131

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Mutations in superoxide dismutase 1 (SOD1) cause familial ALS. Mutant SOD1 preferentially associates with the cytoplasmic face of mitochondria from spinal cords of rats and mice expressing SOD1 mutations. Two-dimensional gels and multidimensional liquid chromatography, in combination with tandem mass spectrometry, revealed 33 proteins that were increased and 21 proteins that were decreased in SOD1G93A rat spinal cord mitochondria compared with SOD1WT spinal cord mitochondria. Analysis of this group of proteins revealed a higher-than-expected proportion involved in complex I and protein import pathways. Direct import assays revealed a 30% decrease in protein import only in spinal cord mitochondria, despite an increase in the mitochondrial import components TOM20, TOM22, and TOM40. Recombinant SOD1 G93A or SOD1 G85R, but not SOD1WT or a Parkinson's disease-causing, misfolded α-synuclein E46K mutant, decreased protein import by >50% in nontransgenic mitochondria from spinal cord, but not from liver. Thus, altered mitochondrial protein content accompanied by selective decreases in protein import into spinal cord mitochondria comprises part of the mitochondrial damage arising from mutant SOD1.motor neuron disease | proteomic | neurodegenerative disease | amyotrophic A myotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disorder caused by loss of the motor neurons within the spinal cord and dysfunction of the motor pathways in the cortex (1, 2). Most cases of ALS (90%) are sporadic. Of the 10% of cases that are inherited, about one-fifth are caused by mutation within the superoxide dismutase 1 (SOD1) gene. Rodents expressing mutant SOD1 develop an ALS-like disease (1, 2). A consensus has emerged that disease arises from acquisition by the mutant proteins of one or more toxic properties, rather than from loss of dismutase activity (3, 4). At least eight prominent mutant-derived toxicities have been proposed, including mitochondrial dysfunction, excitotoxicity, endoplasmic reticulum stress, toxic extracellular SOD1, superoxide production from microglia or astrocytes, and disruption of the blood-brain barrier (5). Furthermore, pathogenesis is noncell autonomous with disease progression driven by mutant synthesis in astrocytes (6-8) and microglia (3, 9).Dysfunction of mitochondria can clearly cause specific damage to neurons or muscle because deletion/mutation in mitochondrial genes causes specific nerve and muscle diseases (10). Accompanying mutant SOD1-mediated disease in some mice is evidence for altered mitochondrial calcium-buffering capacity (11) and changes in the activity of complexes of the electron transport chain (12). Deletion of the mitochondrial BCL-2-related proteins BAX and BAK delays disease onset in SOD1 G93A mice (13), perhaps by modulating effects of SOD1 conformational changes to BCL-2 (14). Apparent damage to mitochondria has been reported in autopsy material from ALS patients (15, 16).Although SOD1 is a primarily cytosolic enzyme, wild-type SOD1 is also found in the intermembrane ...

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Section: Discussionmentioning

confidence: 99%

ALS-linked mutant superoxide dismutase 1 (SOD1) alters mitochondrial protein composition and decreases protein import

Velde²,

Israelson³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

151

131

View full text Add to dashboard Cite

show abstract

“…Interestingly, a meta-analysis of five LOAD case-control studies indicates that rs8106922 is significantly associated with disease risk, with a studywide allelic odds ratio of 2.7 [19]. Several other SNPs in TOMM40 are highly significantly associated with LOAD, some with allelic odds ratios in the 2.8-3.0 range, which provides further evidence for a role for this gene in LOAD [20][21][22][23].…”

mentioning

confidence: 91%

The Importance of Being Connected

Lutz

Crenshaw

Saunders

et al. 2011

JAD

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“…A poly T repeat in an intronic polymorphism (rs10524523) (intron 6) in the TOMM40 gene, which encodes an outer mitochondrial membrane translocase involved in the transport of amyloid-β and other proteins into mitochondria, has been implicated in AD [31][32][33][34][35][36][37][38][39][40][41][42][43][44], and APOE-TOMM40 genotypes have been shown to modify disease risk and age at onset of symptoms [32][33][34][35][36][37]45], although the latter assumption needs replication due to contradictory results [36,[46][47][48][49]. A fixed-effect meta-analysis approach showed that rs4420638 at the TOMM40/APOE/APOC1 gene locus is associated with longevity [50,51].…”

Section: Introductionmentioning

confidence: 99%