High levels of mitochondrial DNA deletions in substantia nigra neurons in aging and Parkinson disease

Bender, Andreas; Krishnan, Kim J.; Morris, Christopher M.; Taylor, Geoffrey A.; Reeve, Amy K.; Perry, Robert H.; Jaros, Evelyn; Hersheson, Joshua; Betts, Joanne; Klopstock, Thomas; Taylor, Robert W.; Turnbull, Douglass M.

doi:10.1038/ng1769

Cited by 1,354 publications

(1,130 citation statements)

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“…The occurrence of parkinsonism associates our families with previously reported CPEO syndromes with parkinsonism and mtDNA multiple deletions due to POLG , C10orf2 , and more recently MPV17 mutations 12, 13, 14. Furthermore, pathologic accumulation of mtDNA multiple deletions in dopaminergic neurons also characterizes idiopathic Parkinson disease, as shown by laser capturing experiments and mtDNA genetic analysis of single neurons from postmortem substantia nigra 15. In our families, parkinsonism was associated with cognitive impairment and, interestingly, Individual III:11, who had dementia without clinical parkinsonism, also had abnormal dopaminergic uptake in the basal ganglia on SPECT/DaT scan (see Fig 4).…”

Section: Discussionsupporting

confidence: 84%

Syndromic parkinsonism and dementia associated with OPA1 missense mutations

Carelli

Musumeci

Caporali

et al. 2015

Annals of Neurology

152

106

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ObjectiveMounting evidence links neurodegenerative disorders such as Parkinson disease and Alzheimer disease with mitochondrial dysfunction, and recent emphasis has focused on mitochondrial dynamics and quality control. Mitochondrial dynamics and mtDNA maintenance is another link recently emerged, implicating mutations in the mitochondrial fusion genes OPA1 and MFN2 in the pathogenesis of multisystem syndromes characterized by neurodegeneration and accumulation of mtDNA multiple deletions in postmitotic tissues. Here, we report 2 Italian families affected by dominant chronic progressive external ophthalmoplegia (CPEO) complicated by parkinsonism and dementia.MethodsPatients were extensively studied by optical coherence tomography (OCT) to assess retinal nerve fibers, and underwent muscle and brain magnetic resonance spectroscopy (MRS), and muscle biopsy and fibroblasts were analyzed. Candidate genes were sequenced, and mtDNA was analyzed for rearrangements.ResultsAffected individuals displayed a slowly progressive syndrome characterized by CPEO, mitochondrial myopathy, sensorineural deafness, peripheral neuropathy, parkinsonism, and/or cognitive impairment, in most cases without visual complains, but with subclinical loss of retinal nerve fibers at OCT. Muscle biopsies showed cytochrome c oxidase‐negative fibers and mtDNA multiple deletions, and MRS displayed defective oxidative metabolism in muscle and brain. We found 2 heterozygous OPA1 missense mutations affecting highly conserved amino acid positions (p.G488R, p.A495V) in the guanosine triphosphatase domain, each segregating with affected individuals. Fibroblast studies showed a reduced amount of OPA1 protein with normal mRNA expression, fragmented mitochondria, impaired bioenergetics, increased autophagy and mitophagy.InterpretationThe association of CPEO and parkinsonism/dementia with subclinical optic neuropathy widens the phenotypic spectrum of OPA1 mutations, highlighting the association of defective mitochondrial dynamics, mtDNA multiple deletions, and altered mitophagy with parkinsonism. Ann Neurol 2015;78:21–38

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Section: Discussionsupporting

confidence: 84%

Syndromic parkinsonism and dementia associated with OPA1 missense mutations

Carelli

Musumeci

Caporali

et al. 2015

Annals of Neurology

152

106

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“…However, in the investigated IPD patients,6 CIV‐negative SN neurons constituted <3% of the total number of analyzed cells, a fraction well below the detection limit in traditional homogenate analysis. In comparison, the postmortem results from Schapira and colleagues4 imply an impairment of CI that is of sufficient magnitude to be detected in SN homogenates.…”

mentioning

confidence: 79%

“…Interestingly, the primary risk factor for PD development is ageing, which is itself correlated with the presence of CIV‐deficient neurons at similar levels to patients with IPD,6, 7 suggesting that age‐related damage accumulation could contribute to neuronal demise in IPD 6, 7…”

mentioning

confidence: 99%

Mitochondrial DNA Depletion in Respiratory Chain–Deficient Parkinson Disease Neurons

Grünewald

Rygiel

Hepplewhite

et al. 2016

Annals of Neurology

196

162

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ObjectiveTo determine the extent of respiratory chain abnormalities and investigate the contribution of mtDNA to the loss of respiratory chain complexes (CI–IV) in the substantia nigra (SN) of idiopathic Parkinson disease (IPD) patients at the single‐neuron level.MethodsMultiple‐label immunofluorescence was applied to postmortem sections of 10 IPD patients and 10 controls to quantify the abundance of CI–IV subunits (NDUFB8 or NDUFA13, SDHA, UQCRC2, and COXI) and mitochondrial transcription factors (TFAM and TFB2M) relative to mitochondrial mass (porin and GRP75) in dopaminergic neurons. To assess the involvement of mtDNA in respiratory chain deficiency in IPD, SN neurons, isolated with laser‐capture microdissection, were assayed for mtDNA deletions, copy number, and presence of transcription/replication‐associated 7S DNA employing a triplex real‐time polymerase chain reaction (PCR) assay.ResultsWhereas mitochondrial mass was unchanged in single SN neurons from IPD patients, we observed a significant reduction in the abundances of CI and II subunits. At the single‐cell level, CI and II deficiencies were correlated in patients. The CI deficiency concomitantly occurred with low abundances of the mtDNA transcription factors TFAM and TFB2M, which also initiate transcription‐primed mtDNA replication. Consistent with this, real‐time PCR analysis revealed fewer transcription/replication‐associated mtDNA molecules and an overall reduction in mtDNA copy number in patients. This effect was more pronounced in single IPD neurons with severe CI deficiency.InterpretationRespiratory chain dysfunction in IPD neurons not only involves CI, but also extends to CII. These deficiencies are possibly a consequence of the interplay between nDNA and mtDNA‐encoded factors mechanistically connected via TFAM. ANN NEUROL 2016;79:366–378

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“…In humans, one of the mechanisms that is believed to be involved in mitochondrial aging is loss of mtDNA integrity and accumulation of mutant mtDNA (Stewart & Chinnery, 2015). The accumulation and clonal expansion of mutant mtDNA are processes that have been causally linked to neurodegeneration and sarcopenia (Bender et al, 2006; Herbst et al, 2016). Metabolic decline, mitochondrial dysfunction, and sarcopenia are all conserved features of aging in C. elegans (Braeckman et al, 2002; Fisher, 2004; Gruber et al, 2011; Herndon et al, 2002; Yasuda et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

“…Later studies confirmed that clonal mtDNA deletions are also present in muscle of healthy, aged humans, where they colocalize with zones of atrophy of muscle fibers and fiber breakage (Bua et al, 2006). In addition to muscle, amplified mtDNA deletions have been reported in substantia nigra neurons in patients with Parkinson disease, suggesting their involvement in some aspects of aging and disease processes in brain as well (Bender et al, 2006). While clonally expanded mtDNA mutations are detected most frequently in postmitotic tissues such as brain and muscle, they may also occur in mitotic tissues such as in colonic epithelium and crypt stem cells (Baines, Turnbull, & Greaves, 2014; McDonald et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Clonal expansion of mitochondrial DNA deletions is a private mechanism of aging in long‐lived animals

Lakshmanan

Yee

et al. 2018

Aging Cell

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Disruption of mitochondrial metabolism and loss of mitochondrial DNA (mtDNA) integrity are widely considered as evolutionarily conserved (public) mechanisms of aging (López‐Otín et al., Cell, 153, 2013 and 1194). Human aging is associated with loss in skeletal muscle mass and function (Sarcopenia), contributing significantly to morbidity and mortality. Muscle aging is associated with loss of mtDNA integrity. In humans, clonally expanded mtDNA deletions colocalize with sites of fiber breakage and atrophy in skeletal muscle. mtDNA deletions may therefore play an important, possibly causal role in sarcopenia. The nematode Caenorhabditis elegans also exhibits age‐dependent decline in mitochondrial function and a form of sarcopenia. However, it is unclear if mtDNA deletions play a role in C. elegans aging. Here, we report identification of 266 novel mtDNA deletions in aging nematodes. Analysis of the mtDNA mutation spectrum and quantification of mutation burden indicates that (a) mtDNA deletions in nematode are extremely rare, (b) there is no significant age‐dependent increase in mtDNA deletions, and (c) there is little evidence for clonal expansion driving mtDNA deletion dynamics. Thus, mtDNA deletions are unlikely to drive the age‐dependent functional decline commonly observed in C. elegans. Computational modeling of mtDNA dynamics in C. elegans indicates that the lifespan of short‐lived animals such as C. elegans is likely too short to allow for significant clonal expansion of mtDNA deletions. Together, these findings suggest that clonal expansion of mtDNA deletions is likely a private mechanism of aging predominantly relevant in long‐lived animals such as humans and rhesus monkey and possibly in rodents.

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High levels of mitochondrial DNA deletions in substantia nigra neurons in aging and Parkinson disease

Cited by 1,354 publications

References 14 publications

Syndromic parkinsonism and dementia associated with OPA1 missense mutations

Syndromic parkinsonism and dementia associated with OPA1 missense mutations

Mitochondrial DNA Depletion in Respiratory Chain–Deficient Parkinson Disease Neurons

Clonal expansion of mitochondrial DNA deletions is a private mechanism of aging in long‐lived animals

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