Frontotemporal dementia and mitochondrial DNA transitions

Grazina, Manuela; Silva, Filipe; Santana, Isabel; Santiago, Beatriz; Mendes, César S.; Simões, Marta; Oliveira, Miguel; Cunha, Luı́s; Oliveira, Catarina

doi:10.1016/j.nbd.2003.11.004

Cited by 12 publications

(8 citation statements)

References 42 publications

(45 reference statements)

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“…Kösel et al [4] found in patients with Parkinson’s disease (PD) a known missense mutation at nucleotide 3338 of the NADH dehydrogenase subunit 1 (ND1) mtDNA gene that changes the amino acid valine to alanine. This mutation has previously been described by Chalmers et al [5] in a control subject, and it was absent in subsets of our PD [6] and frontotemporal dementia [7] patients. …”

Section: Introductionsupporting

confidence: 78%

“…PCR and RFLP of patient and control DNA samples were performed as described previously [6]. When a positive result was found, the fragments of mtDNA were sequenced as reported before [7] and sequences were compared with the revised Cambridge sequence of the human mitochondrial genome [13]. In order to verify if the PCR product was an amplification of mtDNA genes or nuclear pseudogenes, we also analyzed total cellular DNA isolated from ρ⁰ cells.…”

Section: Methodsmentioning

confidence: 99%

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

Grazina

Silva²,

Santana³

et al. 2005

Eur Neurol

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Alzheimer’s disease (AD) is the most common neurodegenerative disorder associated with dementia in late adulthood. Mitochondrial respiratory chain impairment has been detected in the brain, muscle, fibroblasts and platelets of AD patients, indicating a possible involvement of mitochondrial DNA (mtDNA) in the etiology of the disease. Several reports have identified mtDNA mutations in AD patients, but there is no consensual opinion regarding the cause of the impairment. We have studied mtDNA NADH dehydrogenase subunit 1 nucleotides 3337–3340, searching for mutations. Our study group included 129 AD patients and 125 healthy age-matched controls. We have found alterations in two AD patients: one had two already known mtDNA modifications (3197 T-C and 3338 T-C) and the other a novel transition (3199 T-C) which, to our knowledge, has not been described before.

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Section: Introductionsupporting

confidence: 78%

Section: Methodsmentioning

confidence: 99%

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

Grazina

Silva²,

Santana³

et al. 2005

Eur Neurol

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“…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]. Other studies have shown that alterations in the VCP gene induced mitochondrial uncoupling that has been observed in different neurodegenerative diseases [14].…”

Section: Discussionsupporting

confidence: 92%

“…A significant clinical and neuropathological overlap with AD [20] has been described, which may suggest similarities in pathophysiology, including the involvement of mitochondrial DNA (mtDNA) in FTLD, as previously suggested for AD [21,22,23,24]. …”

Section: Introductionmentioning

confidence: 98%

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Genetic Variation of <b><i>MT-ND</i></b> 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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Mitochondrial Respiratory Chain: Biochemical Analysis and Criterion for Deficiency in Diagnosis

Grazina¹

2011

Methods in Molecular Biology

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Spectrophotometric evaluation of mitochondrial respiratory chain (MRC) enzymatic complexes is the main approach to the biochemical investigation and diagnosis in oxidative phosphorylation disorders (also known as mitochondrial cytopathies). Regular dual beam spectrophotometers may be used, but we describe the protocols for double wavelength devices, allowing the analysis of complex activities from a small amount of tissue, with high sensitivity. An important concern is which tissue should be selected for analysis. Accordingly, we present the results obtained with different tissues and control values to be used. There are no standards available for the determinations and no interlaboratory quality control schemes are implemented. Additionally, different laboratories may use different protocols and comparison of results may be difficult. Currently, there is no consensus in literature for defining a criterion of an MRC deficiency to be used in biochemical diagnosis. There is statistical evidence that the most adequate criterion to define an MRC deficiency is below 40% of the mean control value normalized to citrate synthase activity.

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Frontotemporal dementia and mitochondrial DNA transitions

Cited by 12 publications

References 42 publications

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

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

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

Mitochondrial Respiratory Chain: Biochemical Analysis and Criterion for Deficiency in Diagnosis

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