Mitochondrial DNA Variants in a Portuguese Population of Patients with Alzheimer’s Disease

Grazina, Manuela; Silva, Filipe; Santana, Isabel; Pratas, João; Santiago, Beatriz; Oliveira, Miguel; Carreira, Isabel M.; Cunha, Luı́s; Oliveira, Catarina

doi:10.1159/000085555

Cited by 8 publications

(8 citation statements)

References 35 publications

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“…This can suggest that a decrease in complex I activity may be involved in the pathogenesis of the disease. These results are in agreement with previous studies that have also demonstrated mitochondrial impairment activity in related diseases, such as AD, PD, ALS and tauopathies [32,85,86,87,88]. Moreover, our group has previously reported a complex I deficiency in a patient with FTLD [22].…”

Section: Discussionsupporting

confidence: 93%

Genetic Variation of MT-ND Genes in Frontotemporal Lobar Degeneration: Biochemical Phenotype-Genotype Correlation

et al. 2015

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Background: Frontotemporal lobar degeneration (FTLD) is the second most common early-onset dementia. Over the last few decades, a growing number of evidence suggests mitochondrial involvement in neurodegeneration, namely modifications of mitochondrial DNA (mtDNA) contributing to energy impairment. Objective: To sequence the 7 mitochondrially encoded complex I (MT-ND) genes in 70 FTLD patients and investigate mitochondrial respiratory chain (MRC) complex I activity. Methods: A sample of 70 patients was studied (39 females and 31 males; age range: 38-82 years, mean ± SD: 63 ± 11 years) with a probable diagnosis of FTLD. Total DNA was extracted from peripheral blood, and sequencing analysis of 7 MT-ND_n (1, 2, 3, 4L, 4, 5, 6) genes was performed. Variants identified were submitted to in silico study. Spectrophotometric evaluation of MRC activity in lymphocytes was performed, and results were compared with age-matched controls. Results: A total of 358 (161 different) alterations were found in 92.9% of patients. According to in silico analysis of nonsynonymous variants, only 5 variations are possibly or probably damaging. Complex I activity is significantly decreased in patients. Conclusion: To our knowledge, this is the first report of the complete sequence of the MT-ND genes in FTLD patients and correlation with MRC activity. The high number of mtDNA variations identified and a significant decrease in complex I activity suggest a possible involvement of mtDNA alterations in FTLD. Although the majority of these alterations are not primarily pathogenic, an interaction with other mutations may occur, leading to the disease, worsening its expression or influencing age of onset.

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Section: Discussionsupporting

confidence: 93%

Genetic Variation of MT-ND Genes in Frontotemporal Lobar Degeneration: Biochemical Phenotype-Genotype Correlation

et al. 2015

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“…The T-C 3199 transition was described for the first time by our group (Grazina et al 2005). The two patients having the variants 3197C þ 3338C and 3199C (Grazina et al 2005) presented an e3e3 genotype at APO E gene, as the majority of the cases having the 3197C variant, in accordance to what had been described by Egensperger et al (1997) in an AD patient harbouring the A4336G mtDNA mutation.…”

Section: Mitochondrial Dna Mutations and Risk For Adsupporting

confidence: 81%

“…The T-C 3197 transition at the 16S rRNA mtDNA gene, reported earlier in one of our AD patients (Grazina et al 2005), had been previously described (Hess et al 1995) in a patient with ischaemic colitis and in AD, PD, AD þ PD patients and Caucasian controls (Brown et al 1996) as a polymorphism. This polymorphism was also described by Sternberg et al (1998), Arbustini et al (1998), Klemm et al (2001) and Vives-Bauza et al (2002) in control subjects and in patients with mitochondrial disorders, dilated cardiomyopathy, maternal diabetes mellitus and PD patients, respectively.…”

Section: Mitochondrial Dna Mutations and Risk For Adsupporting

confidence: 71%

“…We have recently reported mtDNA variants in two AD patients: in one patient two already known mtDNA modifications (3197 T-C and 3338 T-C) were found and a novel mutation (3199 T-C) was identified (Grazina et al 2005). A significantly higher frequency of the T3197C polymorphism was also detected in AD patients (Table 2) as well as an elevated frequency of e4 allele.…”

Section: Mitochondrial Dna Mutations and Risk For Admentioning

confidence: 85%

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Genetic basis of Alzheimer's dementia: role of mtDNA mutations

Grazina

Pratas

Silva

et al. 2006

Genes Brain and Behavior

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Alzheimer's disease (AD) is the most common neurodegenerative disorder associated to dementia in late adulthood. Amyloid precursor protein, presenilin 1 and presenilin 2 genes have been identified as causative genes for familial AD, whereas apolipoprotein E epsilon4 allele has been associated to the risk for late onset AD. However, mutations on these genes do not explain the majority of cases. Mitochondrial respiratory chain (MRC) impairment has been detected in brain, muscle, fibroblasts and platelets of Alzheimer's patients, indicating a possible involvement of mitochondrial DNA (mtDNA) in the aetiology of the disease. Several reports have identified mtDNA mutations in Alzheimer's patients, suggesting the existence of related causal factors probably of mtDNA origin, thus pointing to the involvement of mtDNA in the risk contributing to dementia, but there is no consensual opinion in finding the cause for impairment. However, mtDNA mutations might modify age of onset, contributing to the neurodegenerative process, probably due to an impairment of MRC and/or translation mechanisms.

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“…Individual mtDNA mutations have been identified in patients with AD (Brown et al, 1996, Edland et al, 1996, Edland et al, 2002, Egensperger et al, 1997, Grazina et al, 2005, Grazina et al, 2006, Hutchin and Cortopassi, 1995, Janetzky et al, 1996, Kosel et al, 1994, Lakatos et al, 2010, Lin et al, 1992, Petruzzella et al, 1992, Qiu et al, 2001, Shoffner et al, 1993, Tanno et al, 1998, Tranah et al, 2012b, Tysoe et al, 1996 and Wragg et al, 1995); yet, many of these studies were small, and most of the identified variants have not been replicated (Edland et al, 2002, Janetzky et al, 1996, Kosel et al, 1994, Petruzzella et al, 1992, Tanno et al, 1998, Tysoe et al, 1996 and Wragg et al, 1995). To date, the most comprehensive studies of mtDNA variation in AD (Lakatos et al, 2010), dementia (Tranah et al, 2012b), and cognitive decline (Tranah et al, 2012b) identified haplogroup and individual variant associations with disease that were independent of APOEε4 allele status.…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial DNA sequence associations with dementia and amyloid-β in elderly African Americans

Tranah

Yokoyama

Katzman

et al. 2014

Neurobiology of Aging

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Mitochondrial dysfunction occurs early in the course of several neurodegenerative diseases, and is potentially related to increased oxidative damage and amyloid-β (Aβ) formation in Alzheimer’s disease. The goals of this study were to assess mtDNA sequence associations with dementia risk, 10-year cognitive change, and markers of oxidative stress and Aβ among 1089 African-Americans in the population-based Health, Aging, and Body Composition Study. Participants were free of dementia at baseline, and incidence was determined in 187 (18%) cases over 10 to 12 follow-up years. Haplogroup L1 participants were at increased risk for developing dementia (odds ratio = 1.88, 95% confidence interval = 1.23–2.88, p = 0.004), lower plasma Aβ42 levels (p = 0.03), and greater 10-year decline on the Digit Symbol Substitution Test (p = 0.04) when compared with common haplogroup L3. The p.V193I, ND2 substitution was associated with significantly higher Aβ42 levels (p = 0.0012), and this association was present in haplogroup L3 (p = 0.018) but not L1 (p = 0.90) participants. All associations were independent of potential confounders, including APOEε4 status and nuclear genetic ancestry. Identification of mtDNA sequence variation associated with dementia risk and cognitive decline may contribute to the development of new treatment targets and diagnostic tests that identify responders to interventions targeting mitochondria.

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Mitochondrial DNA Variants in a Portuguese Population of Patients with Alzheimer’s Disease

Cited by 8 publications

References 35 publications

Genetic Variation of <b><i>MT-ND</i></b> Genes in Frontotemporal Lobar Degeneration: Biochemical Phenotype-Genotype Correlation

Genetic Variation of <b><i>MT-ND</i></b> Genes in Frontotemporal Lobar Degeneration: Biochemical Phenotype-Genotype Correlation

Genetic basis of Alzheimer's dementia: role of mtDNA mutations

Mitochondrial DNA sequence associations with dementia and amyloid-β in elderly African Americans

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