Association of the mitochondrial tRNAA4336G mutation with Alzheimer's and Parkinson's diseases

Abstract

Alzheimer's and Parkinson's diseases (AD, PD) are among the most common neurodegenerative disorders in adults. Both AD and PD have a complex aetiology, and it is widely considered that genetic factors, acting independently or in concert with other genetic and/or environmental factors, modify the risk of developing them. While the apolipoprotein E (ApoE) epsilon 4 allele represents an established risk factor for familial and sporadic late-onset AD, it has been suggested that a common polymorphism in the alpha 1-antichymotrypsin gene modifies the ApoE epsilon 4 dosage effect in AD. Moreover, it has been proposed that a mitochondrial tRNA(Gln) sequence variant (A4336G transition) confers an increased risk for both AD and PD. This finding is of particular interest as the A4336G mutation seems to predispose to two clinically and neuropathologically distinct neurodegenerative disorders. We have examined the allelic frequencies of these putative susceptibility genes in 28 neuropathologically confirmed cases of AD, 23 cases with Lewy-body PD and 100 age-matched controls without clinical or histological evidence of neurodegenerative disease. The ApoE epsilon 4 allele frequency was significantly overrepresented in AD patients vs controls (0.35 vs 0.11) but we could not find evidence for an association between the alpha 1-antichymotrypsin AA genotype, the ApoE epsilon 4 allele and AD. In contrast, the mtDNA(A4336G) mutation was present in one of AD cases and in two of 23 PD patients, whereas no mutation was found in 100 age-matched controls (P < 0.05). Our data therefore support the hypothesis that the mitochondrial A4336G mutation represents a risk factor for AD and PD.

Mitochondrial DNA polymorphisms and risk of Parkinson's disease in Spanish population

“…The 4216C variant was found at an increased frequency in Irish PD cases, but in our population the frequencies for alleles at this SNP did not differ between patients and controls [15]. The mtDNA SNP T4336C has been previously linked to PD [16,24,25]. Interestingly, we found a significantly increased frequency for 4336C in women with PD compared to controls, but this effect was not observed in male patients.…”

Alzheimer's brains harbor somatic mtDNA control-region mutations that suppress mitochondrial transcription and replication

“…Certain germ-line mtDNA mutations have also been associated with lateonset AD. For example, the nucleotide pair (np) 4336 mutation in the tRNA Gln gene has been observed in about 5% of late-onset AD patients (18,19), and this association has been supported in three of four independent European studies (20)(21)(22)(23).…”

Mitochondria and Cell Bioenergetics: Increasingly Recognized Components and a Possible Etiologic Cause of Alzheimer's Disease

“…One of the earliest deviations to be reported was an A4336G transition in the mtDNA tRNA Gln gene (81,122,227,237), although several other studies found no association (48, 80,221,294,306). This transition is characteristic of particular mtDNA haplogroup H subgroups (164,227).…”