Abstract
A common characteristic of neurodegenerative diseases like Alzheimers disease (AD), Parkinsons disease (PD) and Huntingtons disease (HD) is the accumulation of protein aggregates. This reflects a severe disturbance of protein homeostasis, the proteostasis. Here, we review the involvement of the two major proteolytic machineries, the ubiquitin proteasome system (UPS) and the autophagy/lysosomal system, in the pathogenesis of neurodegenerative diseases. These proteolytic systems cooperate to maintain the proteostasis, as is indicated by intricate cross talk. In addition, the UPS and autophagy are regulated by stress pathways that are activated by disturbed proteostasis, like the unfolded protein response (UPR). We will specifically discuss how these proteolytic pathways are affected in neurodegenerative diseases. We will show that there is a differential involvement of the UPS and autophagy in different neurodegenerative disorders. In addition, the proteolytic impairment may be primary or secondary to the pathology. These differences have important implications for the design of therapeutic strategies. The opportunities and caveats of targeting the UPS and autophagy/lysosomal system as a therapeutic strategy in neurodegeneration will be discussed.
Keywords: Autophagy, α-synuclein, neurodegeneration, polyglutamine disorders, proteostasis, tau, ubiquitin proteasome system, unfolded protein response
Current Medicinal Chemistry
Title: Removing Protein Aggregates: The Role of Proteolysis in Neurodegeneration
Volume: 18 Issue: 16
Author(s): D. A.T. Nijholt, L. De Kimpe, H. L. Elfrink, J. J.M. Hoozemans and W. Scheper
Affiliation:
Keywords: Autophagy, α-synuclein, neurodegeneration, polyglutamine disorders, proteostasis, tau, ubiquitin proteasome system, unfolded protein response
Abstract: A common characteristic of neurodegenerative diseases like Alzheimers disease (AD), Parkinsons disease (PD) and Huntingtons disease (HD) is the accumulation of protein aggregates. This reflects a severe disturbance of protein homeostasis, the proteostasis. Here, we review the involvement of the two major proteolytic machineries, the ubiquitin proteasome system (UPS) and the autophagy/lysosomal system, in the pathogenesis of neurodegenerative diseases. These proteolytic systems cooperate to maintain the proteostasis, as is indicated by intricate cross talk. In addition, the UPS and autophagy are regulated by stress pathways that are activated by disturbed proteostasis, like the unfolded protein response (UPR). We will specifically discuss how these proteolytic pathways are affected in neurodegenerative diseases. We will show that there is a differential involvement of the UPS and autophagy in different neurodegenerative disorders. In addition, the proteolytic impairment may be primary or secondary to the pathology. These differences have important implications for the design of therapeutic strategies. The opportunities and caveats of targeting the UPS and autophagy/lysosomal system as a therapeutic strategy in neurodegeneration will be discussed.
Export Options
About this article
Cite this article as:
A.T. Nijholt D., De Kimpe L., L. Elfrink H., J.M. Hoozemans J. and Scheper W., Removing Protein Aggregates: The Role of Proteolysis in Neurodegeneration, Current Medicinal Chemistry 2011; 18 (16) . https://dx.doi.org/10.2174/092986711795843236
DOI https://dx.doi.org/10.2174/092986711795843236 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
Call for Papers in Thematic Issues
Advances in Medicinal Chemistry: From Cancer to Chronic Diseases.
The broad spectrum of the issue will provide a comprehensive overview of emerging trends, novel therapeutic interventions, and translational insights that impact modern medicine. The primary focus will be diseases of global concern, including cancer, chronic pain, metabolic disorders, and autoimmune conditions, providing a broad overview of the advancements in ...read more
Approaches to the treatment of chronic inflammation
Chronic inflammation is a hallmark of numerous diseases, significantly impacting global health. Although chronic inflammation is a hot topic, not much has been written about approaches to its treatment. This thematic issue aims to showcase the latest advancements in chronic inflammation treatment and foster discussion on future directions in this ...read more
Cellular and Molecular Mechanisms of Non-Infectious Inflammatory Diseases: Focus on Clinical Implications
The Special Issue covers the results of the studies on cellular and molecular mechanisms of non-infectious inflammatory diseases, in particular, autoimmune rheumatic diseases, atherosclerotic cardiovascular disease and other age-related disorders such as type II diabetes, cancer, neurodegenerative disorders, etc. Review and research articles as well as methodology papers that summarize ...read more
Chalcogen-modified nucleic acid analogues
Chalcogen-modified nucleosides, nucleotides and oligonucleotides have been of great interest to scientific research for many years. The replacement of oxygen in the nucleobase, sugar or phosphate backbone by chalcogen atoms (sulfur, selenium, tellurium) gives these biomolecules unique properties resulting from their altered physical and chemical properties. The continuing interest in ...read more
![](/images/wayfinder.jpg)
- 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
-
Commentary [Research Highlights (Making Sense Out of Antisense in Huntington’s Disease)]
CNS & Neurological Disorders - Drug Targets The Effect of Statins on the Differentiation and Function of Central Nervous System Cells
Current Medicinal Chemistry L-carnosine and its Derivatives as New Therapeutic Agents for the Prevention and Treatment of Vascular Complications of Diabetes
Current Medicinal Chemistry Preclinical Studies and Clinical Trials with Mesenchymal Stem Cell for Demyelinating Diseases: A Systematic Review
Current Stem Cell Research & Therapy Nanovaccine: A Hope to Triumph the Battle Against Novel Coronavirus Disease 2019 (COVID-19)
Recent Patents on Nanotechnology Correlation Analysis of Capillary APOE, VEGF and eNOS Expression in Alzheimer Brains
Current Alzheimer Research Oxidative Stress Protection by Novel Telomerase Activators in Mesenchymal Stem Cells Derived from Healthy and Diseased Individuals
Current Molecular Medicine A<sub>2A</sub> Adenosine Receptor Antagonists and their Potential in Neurological Disorders
Current Medicinal Chemistry Mitochondrial Biogenesis in Health and Disease. Molecular and Therapeutic Approaches
Current Pharmaceutical Design Recent Patents in CNS Drug Discovery: The Management of Inflammation in the Central Nervous System
Recent Patents on CNS Drug Discovery (Discontinued) The State of the Art of Pyrazole Derivatives as Monoamine Oxidase Inhibitors and Antidepressant/Anticonvulsant Agents
Current Medicinal Chemistry Antioxidants as Potentially Safe Antidotes for Organophosphorus Poisoning
Current Enzyme Inhibition Chronic Kidney Disease and Cardiovascular Disease: Is there Any Relationship?
Current Cardiology Reviews Brain Inflammation is a Common Feature of HIV-Infected Patients without HIV Encephalitis or Productive Brain Infection
Current HIV Research Deciphering the Role of Nanoparticle-based Treatment for Parkinson’s Disease
Current Drug Metabolism Dysfunction of Glutamate Receptors in Microglia May Cause Neurodegeneration
Current Alzheimer Research Induced Pluripotent Stem Cells in Regenerative Medicine and Disease Modeling
Current Stem Cell Research & Therapy Antioxidant Activity of Galantamine and Some of its Derivatives
Current Medicinal Chemistry Getting to Know the Cast - Cellular Interactions and Signaling at the Neurovascular Unit
Current Pharmaceutical Design Nerve Growth Factor: A Focus on Neuroscience and Therapy
Current Neuropharmacology