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
-
Histone Deacetylase Inhibitors in Cancer Treatment: A Review of the Clinical Toxicity and the Modulation of Gene Expression in Cancer Cells
Current Pharmaceutical Biotechnology Patented Small Molecules Used for Reprogramming
Recent Patents on Regenerative Medicine 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 Overview of Brain Tumor Stem Cells – Implications for Treatment
Current Signal Transduction Therapy Castration-resistant Prostate Cancer: Novel Therapeutics Pre- or Post- Taxane Administration
Current Cancer Drug Targets Carbon Nano Tubes: Novel Drug Delivery System in Amelioration of Alzheimer’s Disease
Combinatorial Chemistry & High Throughput Screening Sulfur-based Mechanistic Probes for Enzyme-catalyzed Reactions
Current Medicinal Chemistry Activation of Sphingosine Kinase-1 in Cancer: Implications for Therapeutic Targeting
Current Molecular Pharmacology Role of PARP Inhibitors in Cancer Biology and Therapy
Current Medicinal Chemistry Targeting the p53 Pathway of Apoptosis
Current Pharmaceutical Design Alzheimers Disease: Interactions Between Cholinergic Functions and β- amyloid
Current Alzheimer Research Neuroprotective Mechanisms as Treatment Strategy in Alzheimers disease
Current Medicinal Chemistry - Central Nervous System Agents <i>In Vitro</i> Cytotoxicity and Apoptosis Inducing Evaluation of Novel Halogenated Isatin Derivatives
Anti-Cancer Agents in Medicinal Chemistry Inhibition of Angiogenesis as a Treatment Strategy for Neuroblastoma
Current Cancer Therapy Reviews 5-HT3 Receptors
Current Drug Targets - CNS & Neurological Disorders The Targeted-liposome Delivery System of Antitumor Drugs
Current Drug Metabolism Quantitative Characterization of Phenotypical Markers After Differentiation of SH-SY5Y Cells
CNS & Neurological Disorders - Drug Targets Alzheimers Disease and Oxidative Stress: The Old Problem Remains Unsolved
Current Medicinal Chemistry - Central Nervous System Agents Anticancer Mechanisms of Berberine: A Good Choice for Glioblastoma Multiforme Therapy
Current Medicinal Chemistry Boron Nitride Nanotubes: Production, Properties, Biological Interactions and Potential Applications as Therapeutic Agents in Brain Diseases
Current Nanoscience