Abstract
The presence of protein inclusions within the central nervous system is a characteristic of most neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Aggregates may induce cell death trough several mechanisms, such as sequestration of essential cellular components, clogging of the proteasome system, and/or disruption of axonal transport. The neuropathological signature of ALS is represented by the presence of ubiquitinated inclusions immunoreactive for the protein TDP-43 in the cytoplasm of motor neurons. Recent studies demonstrated that a significant percentage of familial ALS cases are caused by pathogenic mutations in the TAR DNA binding protein and fused in sarcoma/translocated in liposarcoma genes encoding, respectively, for TDP-43 and FUS proteins. Both TDP-43 and FUS are DNA/RNA-binding proteins involved in transcriptional regulation and splicing, shuttling, maturation and transport of mRNA molecules. Mutations in the two genes seem to induce a nucleo-cytoplasmic redistribution of FUS and TDP-43, possibly promoting aggregate formation and/or disrupting their physiological nuclear functions or their interactions with specific RNA targets. Those findings collectively suggest that alterations in cellular RNA metabolism may trigger motor neuron degeneration.
Keywords: TDP-43, FUS, proteinopathies, motor neuron disease, mRNA metabolism
CNS & Neurological Disorders - Drug Targets
Title: Protein Aggregation and Defective RNA Metabolism as Mechanisms for Motor Neuron Damage
Volume: 9 Issue: 3
Author(s): N. Ticozzi, A. Ratti and V. Silani
Affiliation:
Keywords: TDP-43, FUS, proteinopathies, motor neuron disease, mRNA metabolism
Abstract: The presence of protein inclusions within the central nervous system is a characteristic of most neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Aggregates may induce cell death trough several mechanisms, such as sequestration of essential cellular components, clogging of the proteasome system, and/or disruption of axonal transport. The neuropathological signature of ALS is represented by the presence of ubiquitinated inclusions immunoreactive for the protein TDP-43 in the cytoplasm of motor neurons. Recent studies demonstrated that a significant percentage of familial ALS cases are caused by pathogenic mutations in the TAR DNA binding protein and fused in sarcoma/translocated in liposarcoma genes encoding, respectively, for TDP-43 and FUS proteins. Both TDP-43 and FUS are DNA/RNA-binding proteins involved in transcriptional regulation and splicing, shuttling, maturation and transport of mRNA molecules. Mutations in the two genes seem to induce a nucleo-cytoplasmic redistribution of FUS and TDP-43, possibly promoting aggregate formation and/or disrupting their physiological nuclear functions or their interactions with specific RNA targets. Those findings collectively suggest that alterations in cellular RNA metabolism may trigger motor neuron degeneration.
Export Options
About this article
Cite this article as:
Ticozzi N., Ratti A. and Silani V., Protein Aggregation and Defective RNA Metabolism as Mechanisms for Motor Neuron Damage, CNS & Neurological Disorders - Drug Targets 2010; 9 (3) . https://dx.doi.org/10.2174/187152710791292585
DOI https://dx.doi.org/10.2174/187152710791292585 |
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
Techniques of Drug Repurposing: Delivering a new life to Herbs & Drugs
Of late, with the adaptation of innovative approaches and integration of advancements made towards medical sciences as well as the availability of a wide range of tools; several therapeutic challenges are being translated into viable clinical solutions, with a high degree of efficacy, safety, and selectivity. With a better understanding ...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
-
Molecular Mechanism Behind the Synergistic Activity of Diphenylmethyl Selenocyanate and Cisplatin Against Murine Tumor Model
Anti-Cancer Agents in Medicinal Chemistry Irreversible Inhibition of Serine Proteases – Design and In Vivo Activity of Diaryl α-Aminophosphonate Derivatives
Current Medicinal Chemistry MicroRNAs in the Pathobiology of Multiple Myeloma
Current Cancer Drug Targets Recent Advances in the Therapeutic Perspectives of Nutlin-3
Current Pharmaceutical Design B7-H3 Immune Checkpoint Protein in Human Cancer
Current Medicinal Chemistry Interactions of Cnidarian Toxins with the Immune System
Inflammation & Allergy - Drug Targets (Discontinued) The Role of Emerging Genomics and Proteomics Technologies in Cancer Drug Target Discovery
Current Cancer Drug Targets Transductional and Transcriptional Targeting of Adenovirus for Clinical Applications
Current Gene Therapy Positron Emitting Tracers in Pre-Clinical Drug Development
Current Radiopharmaceuticals The Applicability of mTOR Inhibition in Solid Tumors
Current Cancer Drug Targets Small and Long Non-Coding RNAs: Novel Targets in Perspective Cancer Therapy
Current Genomics Clinical Application of Sorafenib for Treating Hepatocellular Carcinoma and Beyond
Clinical Cancer Drugs Supramolecular Nanomedicine - An Overview
Current Drug Targets Nanocarriers in Improving Chemotherapy of Multidrug Resistant Tumors: Key Developments and Perspectives
Current Pharmaceutical Design Alkylphospholipids are Signal Transduction Modulators with Potential for Anticancer Therapy
Anti-Cancer Agents in Medicinal Chemistry Crocins: The Active Constituents of Crocus Sativus L. Stigmas, Exert Significant Cytotoxicity on Tumor Cells In Vitro
Current Cancer Therapy Reviews Withdrawal Notice: Recent Developments in Anti-Cancer Activity of Compounds Containing the Thioether Group
Anti-Cancer Agents in Medicinal Chemistry Measles Virus as An Oncolytic Vector Platform
Current Gene Therapy Blockade of Neoangiogenesis, a New and Promising Technique to Control the Growth of Malignant Tumors and their Metastases
Current Vascular Pharmacology Heart Failure in Sub-Saharan Africa
Current Cardiology Reviews