Somatic mitochondrial DNA mutations in single neurons and glia
Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA. Neurobiology of Aging
(Impact Factor: 5.01).
11/2005; 26(10):1343-55. DOI: 10.1016/j.neurobiolaging.2004.11.008
Somatic mitochondrial DNA (mtDNA) point mutations reach high levels in the brain. However, the cell types that accumulate mutations and the patterns of mutations within individual cells are not known. We have quantified somatic mtDNA mutations in 28 single neurons and in 18 single glia from post-mortem human substantia nigra of six control subjects. Both neurons and glia contain mtDNA with somatic mutations. Single neurons harbor a geometric mean (95% CI) of 200.3 (152.9-262.4) somatic mtDNA point mutations per million base pairs, compared to 133.8 (97.5-184.9) for single glia (p=0.0251). If mutations detected multiple times in the same cell are counted only once, the mean mutation level per million base pairs remains elevated in single neurons (146.9; 124.0-174.2) compared to single glia (100.5; 81.5-126.5; p=0.009). Multiple distinct somatic point mutations are present in different cells from the same subject. Most of these mutations are individually present at low levels (less than 10-20% of mtDNA molecules), but with high aggregate mutation levels, particularly in neurons. These mutations may contribute to changes in brain function during normal aging and neurodegenerative disorders.
Available from: Rafael Castro Fuentes
- "Sporadic mtDNA mutations in single mitochondrias are not enough to induce severe cell damage, but the aggregation of random mutations in an increasing number of mitochondrias can reduce cell viability. This fact probably enhances neurodegeneration in both aged and age-associated diseases such as PD (Cantuti-Castelvetri et al., 2005; Smigrodzki and Khan, 2005; Maruszak et al., 2006). "
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ABSTRACT: Available data show marked similarities for the degeneration of dopamine cells in Parkinson's disease (PD) and aging. The etio-pathogenic agents involved are very similar in both cases, and include free radicals, different mitochondrial disturbances, alterations of the mitophagy and the ubiquitin-proteasome system. Proteins involved in PD such as α-synuclein, UCH-L1, PINK1 or DJ-1, are also involved in aging. The anomalous behavior of astrocytes, microglia and stem cells of the subventricular zone (SVZ) also changes similarly in aging brains and PD. Present data suggest that PD could be the expression of aging on a cell population with high vulnerability to aging. The future knowledge of mechanisms involved in aging could be critical for both understanding the etiology of PD and developing etiologic treatments to prevent the onset of this neurodegenerative illness and to control its progression.
Frontiers in Neuroanatomy 08/2014; 8:80. DOI:10.3389/fnana.2014.00080 · 3.54 Impact Factor
Available from: Anita Pinar
- "Mitochondrial dysfunction comprises a robust hallmark of HD pathology, measurable by cellular dysregulation of key transcripts, deficits in mitochondrial energy capacities, and fusion/fission events (Cantuti-Castelvetri et al., 2005; Cui et al., 2006; Knott et al., 2008; Song et al., 2011b). qRT-PCR analysis of mitochondrial genes PGC-1α, a master regulator of mitochondrial biogenesis and energy metabolism and DRP1, a regulator of mitochondrial fusion and fission showed no consistent differences in transcript levels between both control and HD hESCs or neural differentiated derivatives (Figures 7A,B respectively). "
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ABSTRACT: Huntington's disease (HD) is an incurable neurodegenerative disorder caused by a CAG repeat expansion in exon 1 of the Huntingtin (HTT) gene. Recently, induced pluripotent stem cell (iPSC) lines carrying atypical and aggressive (CAG60+) HD variants have been generated and exhibit disparate molecular pathologies. Here we investigate two human embryonic stem cell (hESC) lines carrying CAG37 and CAG51 typical late-onset repeat expansions in comparison to wildtype control lines during undifferentiated states and throughout forebrain neuronal differentiation. Pluripotent HD lines demonstrate growth, viability, pluripotent gene expression, mitochondrial activity and forebrain specification that is indistinguishable from control lines. Expression profiles of crucial genes known to be dysregulated in HD remain unperturbed in the presence of mutant protein and throughout differentiation; however, elevated glutamate-evoked responses were observed in HD CAG51 neurons. These findings suggest typical late-onset HD mutations do not alter pluripotent parameters or the capacity to generate forebrain neurons, but that such progeny may recapitulate hallmarks observed in established HD model systems. Such HD models will help further our understanding of the cascade of pathological events leading to disease onset and progression, while simultaneously facilitating the identification of candidate HD therapeutics.
Frontiers in Cellular Neuroscience 04/2013; 7:37. DOI:10.3389/fncel.2013.00037 · 4.29 Impact Factor
Available from: Vilhelm A Bohr
- "Mitochondrial DNA (mtDNA) mutations and mitochondrial dysfunction are thought to play an important role in the aging process (Barja, 2004; Cantuti-Castelvetri et al., 2005; Kujoth et al., 2007); and increased levels of oxidative modifications and mutations in mtDNA occur in the brain during normal aging (Beal, 2005; Melov, 2004; Vermulst et al., 2007) and in AD (Gabbita et al., 1998; Morocz et al., 2002). Base excision repair (BER) is the primary DNA repair pathway for small DNA modifications caused by alkylation, deamination or oxidation in nuclei and mitochondria and it has been described to play a major role in the development and maintenance of the central nervous system (CNS) (Weissman et al., 2007a). "
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ABSTRACT: Brain aging is associated with synaptic decline and synaptic function is highly dependent on mitochondria. Increased levels of oxidative DNA base damage and accumulation of mitochondrial DNA (mtDNA) mutations or deletions lead to mitochondrial dysfunction, playing an important role in the aging process and the pathogenesis of several neurodegenerative diseases. Here we have investigated the repair of oxidative base damage, in synaptosomes of mouse brain during normal aging and in an AD model. During normal aging, a reduction in the base excision repair (BER) capacity was observed in the synaptosomal fraction, which was associated with a decrease in the level of BER proteins. However, we did not observe changes between the synaptosomal BER activities of presymptomatic and symptomatic AD mice harboring mutated amyolid precursor protein (APP), Tau, and presinilin-1 (PS1) (3xTgAD). Our findings suggest that the age-related reduction in BER capacity in the synaptosomal fraction might contribute to mitochondrial and synaptic dysfunction during aging. The development of AD-like pathology in the 3xTgAD mouse model was, however, not associated with deficiencies of the BER mechanisms in the synaptosomal fraction when the whole brain was analyzed.
Neurobiology of aging 04/2012; 33(4):694-707. DOI:10.1016/j.neurobiolaging.2010.06.019 · 5.01 Impact Factor
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