Abstract
The pathogenesis of sporadic Parkinsons disease (PD) remains enigmatic. Mitochondrial complex-I defects are known to occur in the substantia nigra (SN) of PD patients and are also debated in some extracerebral tissues. Early sequencing efforts of the mitochondrial DNA (mtDNA) did not reveal specific mutations, but a long lasting discussion was devoted to the issue of randomly distributed low level point mutations, caused by oxidative stress. However, a potential functional impact remained a matter of speculation, since heteroplasmy (mutational load) at any base position analyzed, remained far below the relevant functional threshold. A clearly age-dependent increase of the ‘common mtDNA deletion’ had been demonstrated in most brain regions by several authors since 1992. However, heteroplasmy did hardly exceed 1% of total mtDNA. It became necessary to exploit PCR techniques, which were able to detect any deletion in a few microdissected dopaminergic neurons of the SN. In 2006, two groups published biochemically relevant loads of somatic mtDNA deletions in these neurons. They seem to accumulate to relevant levels in the SN dopaminergic neurons of aged individuals in general, but faster in those developing PD. It is reasonable to assume that this accumulation causes mitochondrial dysfunction of the SN, although it cannot be taken as a final proof for an early pathogenetic role of this dysfunction. Recent studies demonstrate a distribution of deletion breakpoints, which does not differ between PD, aging and classical mitochondrial disorders, suggesting a common, but yet unknown mechanism.
Current Genomics
Title: Do mtDNA Mutations Participate in the Pathogenesis of Sporadic Parkinsons Disease?
Volume: 10 Issue: 8
Author(s): E. Kirches
Affiliation:
Abstract: The pathogenesis of sporadic Parkinsons disease (PD) remains enigmatic. Mitochondrial complex-I defects are known to occur in the substantia nigra (SN) of PD patients and are also debated in some extracerebral tissues. Early sequencing efforts of the mitochondrial DNA (mtDNA) did not reveal specific mutations, but a long lasting discussion was devoted to the issue of randomly distributed low level point mutations, caused by oxidative stress. However, a potential functional impact remained a matter of speculation, since heteroplasmy (mutational load) at any base position analyzed, remained far below the relevant functional threshold. A clearly age-dependent increase of the ‘common mtDNA deletion’ had been demonstrated in most brain regions by several authors since 1992. However, heteroplasmy did hardly exceed 1% of total mtDNA. It became necessary to exploit PCR techniques, which were able to detect any deletion in a few microdissected dopaminergic neurons of the SN. In 2006, two groups published biochemically relevant loads of somatic mtDNA deletions in these neurons. They seem to accumulate to relevant levels in the SN dopaminergic neurons of aged individuals in general, but faster in those developing PD. It is reasonable to assume that this accumulation causes mitochondrial dysfunction of the SN, although it cannot be taken as a final proof for an early pathogenetic role of this dysfunction. Recent studies demonstrate a distribution of deletion breakpoints, which does not differ between PD, aging and classical mitochondrial disorders, suggesting a common, but yet unknown mechanism.
Export Options
About this article
Cite this article as:
Kirches E., Do mtDNA Mutations Participate in the Pathogenesis of Sporadic Parkinsons Disease?, Current Genomics 2009; 10 (8) . https://dx.doi.org/10.2174/138920209789503879
DOI https://dx.doi.org/10.2174/138920209789503879 |
Print ISSN 1389-2029 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5488 |
Call for Papers in Thematic Issues
Current Genomics in Cardiovascular Research
Cardiovascular diseases are the main cause of death in the world, in recent years we have had important advances in the interaction between cardiovascular disease and genomics. In this Research Topic, we intend for researchers to present their results with a focus on basic, translational and clinical investigations associated with ...read more
Deep learning in Single Cell Analysis
The field of biology is undergoing a revolution in our ability to study individual cells at the molecular level, and to integrate data from multiple sources and modalities. This has been made possible by advances in technologies for single-cell sequencing, multi-omics profiling, spatial transcriptomics, and high-throughput imaging, as well as ...read more
New insights on Pediatric Tumors and Associated Cancer Predisposition Syndromes
Because of the broad spectrum of children cancer susceptibility, the diagnosis of cancer risk syndromes in children is rarely used in direct cancer treatment. The field of pediatric cancer genetics and genomics will only continue to expand as a result of increasing use of genetic testing tools. It's possible that ...read more
Related Journals
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements
Related Articles
-
Improving the Stability of Aptamers by Chemical Modification
Current Medicinal Chemistry Cyclotron Production of PET Radiometals in Liquid Targets: Aspects and Prospects
Current Radiopharmaceuticals Spirulina paltensis: Food and Function
Current Nutrition & Food Science Resveratrol and Neurodegenerative Diseases: Activation of SIRT1 as the Potential Pathway towards Neuroprotection
Current Neurovascular Research Intracellular Aβ and its Pathological Role in Alzheimer’s Disease: Lessons from Cellular to Animal Models
Current Alzheimer Research FAK and Nanog Cross Talk with p53 in Cancer Stem Cells
Anti-Cancer Agents in Medicinal Chemistry Insights Into Effects of Ellagic Acid on the Nervous System: A Mini Review
Current Pharmaceutical Design Molecular Targets of Tannic Acid in Alzheimer's Disease
Current Alzheimer Research Proteomics Approaches to Understand Linkage Between Alzheimer’s Disease and Type 2 Diabetes Mellitus
CNS & Neurological Disorders - Drug Targets Marginal Vitamin A Deficiency Exacerbates Memory Deficits Following Aβ1-42 Injection in Rats
Current Alzheimer Research Recent Highlights on Molecular Hybrids Potentially Useful in Central Nervous System Disorders
Mini-Reviews in Medicinal Chemistry Cellular and Molecular Regulation of Inflammatory Pain, Nociception and Hyperalgesia - The Role of the Transcription Factor NF-κB as the Lynchpin Nocisensor: Hyperalgesic or Analgesic Effect?
Current Immunology Reviews (Discontinued) Polyisoprenylation Potentiates the Inhibition of Polyisoprenylated Methylated Protein Methyl Esterase and the Cell Degenerative Effects of Sulfonyl Fluorides
Current Cancer Drug Targets Interactions of Iron Oxide Nanoparticles with the Immune System: Challenges and Opportunities for their Use in Nano-oncology
Current Pharmaceutical Design Modulation of k-Ras Signaling by Natural Products
Current Medicinal Chemistry Cell Arrest and Apoptosis Induced by the Next Generation of Vanadium Based Drugs: Action Mechanism to Structure Relation and Future Perspectives
Anti-Cancer Agents in Medicinal Chemistry Biospecies Capture and Detection at Low Concentration
Micro and Nanosystems Colostral Proline-Rich Polypeptides - Immunoregulatory Properties and Prospects of Therapeutic Use in Alzheimers Disease
Current Alzheimer Research Hypericin - The Facts About a Controversial Agent
Current Pharmaceutical Design Neurotransmitters and Microglial-Mediated Neuroinflammation
Current Protein & Peptide Science