Abstract
Idiopathic Parkinsons Disease (PD) is a progressive neurodegenerative disease characterized by dopaminergic neuronal loss within the substantia nigra. The degeneration of dopamine and other neuronal populations in PD lead to both chronic motor and non-motor disabilities but the mechanisms remain unclear. Molecular genetic studies in familial forms of the disease identified key proteins involved in PD pathogenesis, supporting a major role for (i) protein aggregation and neurotoxic α-synuclein oligomeric species due to an altered protein quality control, (ii) parkin-driven deregulation of the ubiquitin-proteasome system, (iii) oxidative stress and mithocondrial dysfunction, and, finally, (iv) disturbed kinase activity. The elucidation of these new molecular pathways has increased our knowledge of PD pathophysiology, but it remains an open question whether alterations of these pathways lead to different entities of PD or whether they finally converge at a point that is the common pathogenetic denominator of PD. However, the knowledge of validated targets is in its infancy, and thus, traditional target-based drug discovery strategies are of limited use. Alternative approaches are needed, and early attempts were aimed at identifying molecules inhibiting the aggregation of α-synuclein fragments, interfering with the ubiquitin proteasome pathway and reducing oxidative stress. Such discovery strategies have an impact on the configuration of screening cascades for effective translation of drug candidates toward clinical trials. This review examines how these genetic findings provided us with suitable animal models and how the gained insights will contribute to better therapies for PD.
Keywords: Parkinson's disease, ubiquitin-proteasome system, parkin, autophagy, α-Synuclein, UCH-L1 (ubiquitin carboxyterminal hydrolase L1), DJ-1, Pink1 (PTEN-induced kinase 1), Leucine-rich repeat kinase 2 (LRRK2), Dopaminergic neurons
Current Topics in Medicinal Chemistry
Title: New Molecular Avenues in Parkinson ’ s Disease Therapy
Volume: 9 Issue: 10
Author(s): Mario Di Napoli
Affiliation:
Keywords: Parkinson's disease, ubiquitin-proteasome system, parkin, autophagy, α-Synuclein, UCH-L1 (ubiquitin carboxyterminal hydrolase L1), DJ-1, Pink1 (PTEN-induced kinase 1), Leucine-rich repeat kinase 2 (LRRK2), Dopaminergic neurons
Abstract: Idiopathic Parkinsons Disease (PD) is a progressive neurodegenerative disease characterized by dopaminergic neuronal loss within the substantia nigra. The degeneration of dopamine and other neuronal populations in PD lead to both chronic motor and non-motor disabilities but the mechanisms remain unclear. Molecular genetic studies in familial forms of the disease identified key proteins involved in PD pathogenesis, supporting a major role for (i) protein aggregation and neurotoxic α-synuclein oligomeric species due to an altered protein quality control, (ii) parkin-driven deregulation of the ubiquitin-proteasome system, (iii) oxidative stress and mithocondrial dysfunction, and, finally, (iv) disturbed kinase activity. The elucidation of these new molecular pathways has increased our knowledge of PD pathophysiology, but it remains an open question whether alterations of these pathways lead to different entities of PD or whether they finally converge at a point that is the common pathogenetic denominator of PD. However, the knowledge of validated targets is in its infancy, and thus, traditional target-based drug discovery strategies are of limited use. Alternative approaches are needed, and early attempts were aimed at identifying molecules inhibiting the aggregation of α-synuclein fragments, interfering with the ubiquitin proteasome pathway and reducing oxidative stress. Such discovery strategies have an impact on the configuration of screening cascades for effective translation of drug candidates toward clinical trials. This review examines how these genetic findings provided us with suitable animal models and how the gained insights will contribute to better therapies for PD.
Export Options
About this article
Cite this article as:
Di Napoli Mario, New Molecular Avenues in Parkinson ’ s Disease Therapy, Current Topics in Medicinal Chemistry 2009; 9 (10) . https://dx.doi.org/10.2174/156802609789378254
DOI https://dx.doi.org/10.2174/156802609789378254 |
Print ISSN 1568-0266 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4294 |
Call for Papers in Thematic Issues
Chemistry Based on Natural Products for Therapeutic Purposes
The development of new pharmaceuticals for a wide range of medical conditions has long relied on the identification of promising natural products (NPs). There are over sixty percent of cancer, infectious illness, and CNS disease medications that include an NP pharmacophore, according to the Food and Drug Administration. Since NP ...read more
Current Trends in Drug Discovery Based on Artificial Intelligence and Computer-Aided Drug Design
Drug development discovery has faced several challenges over the years. In fact, the evolution of classical approaches to modern methods using computational methods, or Computer-Aided Drug Design (CADD), has shown promising and essential results in any drug discovery campaign. Among these methods, molecular docking is one of the most notable ...read more
Drug Discovery in the Age of Artificial Intelligence
In the age of artificial intelligence (AI), we have witnessed a significant boom in AI techniques for drug discovery. AI techniques are increasingly integrated and accelerating the drug discovery process. These developments have not only attracted the attention of academia and industry but also raised important questions regarding the selection ...read more
From Biodiversity to Chemical Diversity: Focus of Flavonoids
Flavonoids are the largest group of polyphenols, plant secondary metabolites arising from the essential aromatic amino acid phenylalanine (or more rarely from tyrosine) via the phenylpropanoid pathway. The flavan nucleus is the basic 15-carbon skeleton of flavonoids (C6-C3-C6), which consists of two phenyl rings (A and B) and a heterocyclic ...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
- Announcements
Related Articles
-
Investigation on the Molecular Interactions Stabilizing the Structure of α-synuclein Fibril: An In silico Study
Central Nervous System Agents in Medicinal Chemistry Influence of Statin Use on Endothelial Function: From Bench to Clinics
Current Pharmaceutical Design Synthesis and Biological Activities of Substituted Benzoxazepine: A Review
Mini-Reviews in Organic Chemistry MicroRNA and Multiple Myeloma: from Laboratory Findings to Translational Therapeutic Approaches
Current Pharmaceutical Biotechnology Substance P and Alzheimer’s Disease: Emerging Novel Roles
Current Alzheimer Research Targeted Delivery for Neurodegenerative Disorders Using Gene Therapy Vectors: Gene Next Therapeutic Goals
Current Gene Therapy Specific Targeting of Akt Kinase Isoforms: Taking the Precise Path for Prevention and Treatment of Cancer
Current Drug Targets Neurological Disorders of Purine and Pyrimidine Metabolism
Current Topics in Medicinal Chemistry Immune Checkpoint Inhibitors: Basics and Challenges
Current Medicinal Chemistry Multimodality Imaging of CXCR4 in Cancer: Current Status towards Clinical Translation
Current Molecular Medicine Transient Receptor Potential Channels - Emerging Novel Drug Targets for the Treatment of Pain
Current Medicinal Chemistry Withdrawal Notice: Role, Significance and Association of microRNA-10a/b in Physiology of Cancer
MicroRNA Protein Interaction Domains: Structural Features and Drug Discovery Applications (Part 2)
Current Medicinal Chemistry Molecular Mechanism Aspect of ER Stress in Alzheimer's Disease: Current Approaches and Future Strategies
Current Drug Targets Targeting Apoptosis Resistance in Rhabdomyosarcoma
Current Cancer Drug Targets Antineoplastic Potential of Medicinal Plants
Recent Patents on Biotechnology Roles of Nicotinic Acetylcholine Receptors in Stem Cell Survival/Apoptosis, Proliferation and Differentiation
Current Molecular Medicine A Review of Depsipeptide and Other Histone Deacetylase Inhibitors in Clinical Trials
Current Pharmaceutical Design Tubulin-Independent Tau in Alzheimer’s Disease and Cancer: Implications for Disease Pathogenesis and Treatment
Current Alzheimer Research Chemical Composition and In Vitro Neuroprotective Activity of Fibre-Type Cannabis sativa L. (Hemp)
Current Bioactive Compounds