Article

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: 11.91). 06/2012; 71(6):850-4. DOI: 10.1002/ana.23568
Source: PubMed

ABSTRACT 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.

0 Followers
 · 
101 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Following the observation of increased oxidative DNA damage in nuclear and mitochondrial DNA extracted from post-mortem brain regions of patients affected by neurodegenerative diseases, the last years of the previous century and the first decade of the present one have been largely dedicated to the search of markers of DNA damage in neuronal samples and peripheral tissues of patients in early, intermediate or late stages of neurodegeneration. Those studies allowed to demonstrate that oxidative DNA damage is one of the earliest detectable events in neurodegeneration, but also revealed cytogenetic damage in neurodegenerative conditions, such as for example a tendency towards chromosome 21 malsegregation in Alzheimer's disease. As it happens for many neurodegenerative risk factors the question of whether DNA damage is cause or consequence of the neurodegenerative process is still open, and probably both is true. The research interest in markers of oxidative stress was shifted, in recent years, towards the search of epigenetic biomarkers of neurodegenerative disorders, following the accumulating evidence of a substantial contribution of epigenetic mechanisms to learning, memory processes, behavioural disorders and neurodegeneration. Increasing evidence is however linking DNA damage and repair with epigenetic phenomena, thereby opening the way to a very attractive and timely research topic in neurodegenerative diseases. We will address those issues in the context of Alzheimer's disease, Parkinson's disease, and Amyotrophic Lateral Sclerosis, which represent three of the most common neurodegenerative pathologies in humans.
    Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis 12/2014; DOI:10.1016/j.mrfmmm.2014.11.010 · 4.44 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Neurodegenerative diseases are characterized by selective and progressive degeneration of neuronal population in the brain, and associated behavioural, motor, psychiatric and cognitive impairments. Aggregation of pathogenic proteins, mitochondrial dysfunction, oxidative stress, transcriptional dysfunction and apoptosis play an important role in pathogenesis of neurodegenerative disorders such as Parkinson's disease, Huntington's disease, Alzheimer's disease and Amyotrophic lateral sclerosis. Here, we provide a concise overview of the major findings about the therapeutic role of peptides such as neurotrophins, neurotrophic factors (NGF, BDNF and GDNF), neuropeptides, mitochondrial targeted antioxidants/peptides, MitoQ, neurturin, and β-sheet breaker peptides in neurodegenerative disorders.
    Current Medicinal Chemistry 02/2014; DOI:10.2174/0929867321666140217125857 · 3.72 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Mitochondrial defects have been shown to be associated with the pathogenesis of Parkinson's disease (PD). Yet, experience in PD research linking mitochondrial dysfunction, e.g., deregulation of oxidative phosphorylation, with neuronal degeneration and behavioral changes is rather limited. Using the 6-hydroxydopamine (6-OHDA) rat model of PD, we have investigated the potential role of mitochondria in dopaminergic neuronal cell death in the substantia nigra pars compacta by high-resolution respirometry. Mitochondrial function was correlated with the time course of disease-related motor behavior asymmetry and dopaminergic neuronal cell loss, respectively. Unilateral 6-OHDA injections (>2.5 μg/2 μl) into the median forebrain bundle induced an impairment of oxidative phosphorylation due to a decrease in complex I activity. This was indicated by increased flux control coefficient. During the period of days 2-21, a progressive decrease in respiratory control ratio of up to -58 % was observed in the lesioned compared to the non-lesioned substantia nigra of the same animals. This decrease was associated with a marked uncoupling of oxidative phosphorylation. Mitochondrial dysfunction, motor behavior asymmetry, and dopaminergic neuronal cell loss correlated with dosage (1.25-5 μg/2 μl). We conclude that high-resolution respirometry may allow the detection of distinct mitochondrial dysfunction as a suitable surrogate marker for the preclinical assessment of potential neuroprotective strategies in the 6-OHDA model of PD.
    Journal of Neural Transmission 03/2014; 121(10). DOI:10.1007/s00702-014-1185-3 · 2.87 Impact Factor

Full-text (2 Sources)

Download
57 Downloads
Available from
May 19, 2014