Abstract
One of the critical issues in Parkinson disease (PD) research is the identity of the specific toxic, pathogenic moiety. In PD, mutations in alpha-synuclein (αsyn) or multiplication of the SNCA gene encoding αsyn, result in a phenotype of cellular inclusions, cell death, and brain dysfunction. While the historical point of view has been that the macroscopic aggregates containing αsyn are the toxic species, in the last several years evidence has emerged that suggests instead that smaller soluble species - likely oligomers containing misfolded αsyn - are actually the toxic moiety and that the fibrillar inclusions may even be a cellular detoxification pathway and less harmful. If soluble misfolded species of αsyn are the toxic moieties, then cellular mechanisms that degrade misfolded αsyn would be neuroprotective and a rational target for drug development. In this review we will discuss the fundamental mechanisms underlying αsyn toxicity including oligomer formation, oxidative stress, and degradation pathways and consider rational therapeutic strategies that may have the potential to prevent or halt αsyn induced pathogenesis in PD.
Keywords: Alpha-synuclein, Parkinson's Disease, Chaperones, Oligomers, Heat shock proteins, oxidative stress, Degradation, Neurodegeneration, AMPA, MPTP, PINK1, Geldanamycin, Gene therapy, CHIP, Chaperone-mediated autophagy
CNS & Neurological Disorders - Drug Targets
Title: Drug Targets from Genetics: Alpha-Synuclein
Volume: 10 Issue: 6
Author(s): Karin M. Danzer and Pamela J. McLean
Affiliation:
Keywords: Alpha-synuclein, Parkinson's Disease, Chaperones, Oligomers, Heat shock proteins, oxidative stress, Degradation, Neurodegeneration, AMPA, MPTP, PINK1, Geldanamycin, Gene therapy, CHIP, Chaperone-mediated autophagy
Abstract: One of the critical issues in Parkinson disease (PD) research is the identity of the specific toxic, pathogenic moiety. In PD, mutations in alpha-synuclein (αsyn) or multiplication of the SNCA gene encoding αsyn, result in a phenotype of cellular inclusions, cell death, and brain dysfunction. While the historical point of view has been that the macroscopic aggregates containing αsyn are the toxic species, in the last several years evidence has emerged that suggests instead that smaller soluble species - likely oligomers containing misfolded αsyn - are actually the toxic moiety and that the fibrillar inclusions may even be a cellular detoxification pathway and less harmful. If soluble misfolded species of αsyn are the toxic moieties, then cellular mechanisms that degrade misfolded αsyn would be neuroprotective and a rational target for drug development. In this review we will discuss the fundamental mechanisms underlying αsyn toxicity including oligomer formation, oxidative stress, and degradation pathways and consider rational therapeutic strategies that may have the potential to prevent or halt αsyn induced pathogenesis in PD.
Export Options
About this article
Cite this article as:
M. Danzer Karin and J. McLean Pamela, Drug Targets from Genetics: Alpha-Synuclein, CNS & Neurological Disorders - Drug Targets 2011; 10 (6) . https://dx.doi.org/10.2174/187152711797247867
DOI https://dx.doi.org/10.2174/187152711797247867 |
Print ISSN 1871-5273 |
Publisher Name Bentham Science Publisher |
Online ISSN 1996-3181 |
Call for Papers in Thematic Issues
Diagnosis and treatment of central nervous system infectious diseases
Infectious diseases of the central nervous system (CNS) can be divided into bacterial, tuberculous, viral, fungal, parasitic infections, etc. Early etiological treatment is often the most crucial means to reduce the mortality rate of patients with central nervous system infections, reduce complications and sequelae, and improve prognosis. The initial clinical ...read more
Trends and perspectives in the rational management of CNS disorders
Central nervous system (CNS) diseases enforce a significant global health burden, driving ongoing efforts to improve our understanding and effectiveness of therapy. This issue investigates current advances in the discipline, focusing on the understanding as well as therapeutic handling of various CNS diseases. The issue covers a variety of diseases, ...read more
- 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
Related Articles
-
Involvement of Targeting and Scaffolding Proteins in the Regulation of the EGFR/Ras/MAPK Pathway in Oncogenesis
Current Signal Transduction Therapy Effects of Early Maternal Separation on Biobehavioral and Neuropathological Markers of Alzheimer's Disease in Adult Male Rats
Current Alzheimer Research Benzofuran Small Molecules as Potential Inhibitors of Human Protein Kinases. A Review
Current Pharmaceutical Design Metastasis Suppressors: Basic and Translational Advances
Current Pharmaceutical Biotechnology Utilization of Lipid-based Nanoparticles to Improve the Therapeutic Benefits of Bortezomib
Anti-Cancer Agents in Medicinal Chemistry Enasidenib: First Mutant IDH2 Inhibitor for the Treatment of Refractory and Relapsed Acute Myeloid Leukemia
Anti-Cancer Agents in Medicinal Chemistry Application of NMR to the Study of Cells and Body Fluids
Current Organic Chemistry Amyloid Precursor Protein Processing in Vivo - Insights from a Chemically- Induced Constitutive Overactivation of Protein Kinase C in Guinea Pig Brain
Current Medicinal Chemistry GqPCR-mediated Signalling in the Spotlight: From Visualization Towards Dissection and Quantification
Current Pharmaceutical Biotechnology Is there a Role for Epigenetic Enhancement of Immunomodulatory Approaches to Cancer Treatment?
Current Cancer Drug Targets A Review of Pediatric Mediastinal Masses and Castlemans Disease
Current Pediatric Reviews Establishment of Cholinergic Neuron-like Cell Lines with Differential Vulnerability to Nitrosative Stress
Current Neurovascular Research Separation of Ginseng Active Ingredients and their Roles in Cancer Metastasis Supplementary Therapy
Current Drug Metabolism Dual-Specificity MAP Kinase Phosphatases as Targets of Cancer Treatment
Anti-Cancer Agents in Medicinal Chemistry MYC as Therapeutic Target for Embryonal Tumors: Potential and Challenges
Current Cancer Drug Targets Protein Aggregation in Alzheimers Disease and Other Neoropathological Disorders
Current Alzheimer Research Bispidine as a Privileged Scaffold
Current Topics in Medicinal Chemistry Pyrrolo[2,3-d]Pyrimidines as Kinase Inhibitors
Current Medicinal Chemistry Inhibitor at the Gates, Inhibitor in the Chamber: Allosteric and Competitive Inhibitors of the Proteasome as Prospective Drugs
Current Medicinal Chemistry - Immunology, Endocrine & Metabolic Agents Indolo[2,3-a]quinolizidines and Derivatives: Bioactivity and Asymmetric Synthesis
Current Pharmaceutical Design