Somatic mitochondrial DNA mutations in early Parkinson and incidental Lewy body disease

Department of Neurology and Neuroscience, Weill Cornell Medical College, New York, NY, USA.
Annals of Neurology (Impact Factor: 9.98). 06/2012; 71(6):850-4. DOI: 10.1002/ana.23568
Source: PubMed


Somatic mutations in mitochondrial DNA (mtDNA) are hypothesized to play a role in Parkinson disease (PD), but large increases in mtDNA mutations have not previously been found in PD, potentially because neurons with high mutation levels degenerate and thus are absent in late stage tissue. To address this issue, we studied early stage PD cases and cases of incidental Lewy body disease (ILBD), which is thought to represent presymptomatic PD. We show for the first time that mtDNA mutation levels in substantia nigra neurons are significantly elevated in this group of early PD and ILBD cases.

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    • "Because post-mortem tissue from patients with Parkinson's disease usually represents late stages of the disease, one can hypothesize that substantia nigra pars compacta dopaminergic cells still present in late-stage disease may be those accumulating fewer mitochondrial DNA deletions (560%) whereas neurons that have already been lost in these brains might have had higher levels (460%) of mitochondrial DNA deletions. Supporting this possibility, a recent study reported higher levels of somatic mitochondrial DNA point mutations in nigral neurons from early-stage Parkinson's disease cases and cases with incidental Lewy body disease, which may represent an early presymptomatic stage of Parkinson's disease, compared with late-stage Parkinson's disease cases or controls (Lin et al., 2012). "
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    ABSTRACT: Acquired alterations in mitochondrial DNA are believed to play a pathogenic role in Parkinson's disease. In particular, accumulation of mitochondrial DNA deletions has been observed in substantia nigra pars compacta dopaminergic neurons from patients with Parkinson's disease and aged individuals. Also, mutations in mitochondrial DNA polymerase gamma result in multiple mitochondrial DNA deletions that can be associated with levodopa-responsive parkinsonism and severe substantia nigra pars compacta dopaminergic neurodegeneration. However, whether mitochondrial DNA deletions play a causative role in the demise of dopaminergic neurons remains unknown. Here we assessed the potential pathogenic effects of mitochondrial DNA deletions on the dopaminergic nigrostriatal system by using mutant mice possessing a proofreading-deficient form of mitochondrial DNA polymerase gamma (POLG(D257A)), which results in a time-dependent accumulation of mitochondrial DNA deletions in several tissues, including the brain. In these animals, we assessed the occurrence of mitochondrial DNA deletions within individual substantia nigra pars compacta dopaminergic neurons, by laser capture microdissection and quantitative real-time polymerase chain reaction, and determined the potential deleterious effects of such mitochondrial DNA alterations on mitochondrial function and dopaminergic neuronal integrity, by cytochrome c oxidase histochemistry and quantitative morphology. Nigral dopaminergic neurons from POLG(D257A) mice accumulate mitochondrial DNA deletions to a similar extent (∼40-60%) as patients with Parkinson's disease and aged individuals. Despite such high levels of mitochondrial DNA deletions, the majority of substantia nigra pars compacta dopaminergic neurons from these animals did not exhibit mitochondrial dysfunction or degeneration. Only a few individual substantia nigra pars compacta neurons appeared as cytochrome c oxidase-negative, which exhibited higher levels of mitochondrial DNA deletions than cytochrome c oxidase-positive cells (60.38 ± 3.92% versus 45.18 ± 2.83%). Survival of dopaminergic neurons in POLG(D257A) mice was associated with increased mitochondrial DNA copy number, enhanced mitochondrial cristae network, improved mitochondrial respiration, decreased exacerbation of mitochondria-derived reactive oxygen species, greater striatal dopamine levels and resistance to parkinsonian mitochondrial neurotoxins. These results indicate that primary accumulation of mitochondrial DNA deletions within substantia nigra pars compacta dopaminergic neurons, at an extent similar to that observed in patients with Parkinson's disease, do not kill dopaminergic neurons but trigger neuroprotective compensatory mechanisms at a mitochondrial level that may account for the high pathogenic threshold of mitochondrial DNA deletions in these cells.
    Full-text · Article · Aug 2013 · Brain
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    • "The concept of spread of neurodegenerative disease from a small focus of cells with a somatic mutation has already been proposed, with particular emphasis on amyotrophic lateral sclerosis.12,50 In this scenario, a negative result in brain-derived DNA would not exclude an initiating somatic mutation, which would be extremely difficult to detect, as neurons carrying it would be among the first to die after triggering the pathogenic process; a similar issue was discussed in relation to mtDNA mutations, with SN neurons with high mtDNA mutation levels likely to be lost early in the disease course.34 It is clear that harboring a SNCA mutation is not enough to lead to death of any type of neuron, as even in cases with inherited mutations, which all neurons carry, the distribution of pathology is very specific.51 "
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    ABSTRACT: Alpha-synuclein (SNCA) is crucial in the pathogenesis of Parkinson's disease (PD), yet mutations in the SNCA gene are rare. Evidence for somatic genetic variation in normal humans, also involving the brain, is increasing, but its role in disease is unknown. Somatic SNCA mutations, arising in early development and leading to mosaicism, could contribute to PD pathogenesis and yet be absent or undetectable in DNA derived from peripheral lymphocytes. Such mutations could underlie the widespread pathology in PD, with the precise clinical outcome dependent on their type and the timing and location of their occurrence. We recently reported a novel SNCA mutation (c.150T>G, p.H50Q) in PD brain-derived DNA. To determine if there was mosaicism for this, a PCR and cloning strategy was used to take advantage of a nearby heterozygous intronic polymorphism. No evidence of mosaicism was found. High-resolution melting curve analysis of SNCA coding exons, which was shown to be sensitive enough to detect low proportions of 2 known mutations, did not reveal any further mutations in DNA from 28 PD brain-derived samples. We outline the grounds that make the somatic SNCA mutation hypothesis consistent with genetic, embryological, and pathological data. Further studies of brain-derived DNA are warranted and should include DNA from multiple regions and methods for detecting other types of genomic variation. © 2013 Movement Disorder Society.
    Full-text · Article · Jun 2013 · Movement Disorders

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