Emerging mechanisms of molecular pathology in ALS.

TitleEmerging mechanisms of molecular pathology in ALS.
Publication TypeJournal Article
Year of Publication2015
AuthorsPeters, OM, Ghasemi, M, Brown, RH
JournalJ Clin Invest
Volume125
Issue5
Pagination1767-1779
Date Published2015 May
ISSN1558-8238
KeywordsAmyotrophic Lateral Sclerosis, Animals, Axonal Transport, Axons, Cytoskeleton, DNA-Binding Proteins, Genetic Association Studies, Genetic Therapy, Humans, Inflammation, Mice, Mice, Transgenic, Molecular Targeted Therapy, Motor Neurons, Nerve Tissue Proteins, Neuroglia, Oxidative Stress, Protein Aggregation, Pathological, Protein Processing, Post-Translational, Proteolysis, RNA-Binding Proteins, Superoxide Dismutase, Superoxide Dismutase-1, Ubiquitination
Abstract

Amyotrophic lateral sclerosis (ALS) is a devastating degenerative disease characterized by progressive loss of motor neurons in the motor cortex, brainstem, and spinal cord. Although defined as a motor disorder, ALS can arise concurrently with frontotemporal lobal dementia (FTLD). ALS begins focally but disseminates to cause paralysis and death. About 10% of ALS cases are caused by gene mutations, and more than 40 ALS-associated genes have been identified. While important questions about the biology of this disease remain unanswered, investigations of ALS genes have delineated pathogenic roles for (a) perturbations in protein stability and degradation, (b) altered homeostasis of critical RNA- and DNA-binding proteins, (c) impaired cytoskeleton function, and (d) non-neuronal cells as modifiers of the ALS phenotype. The rapidity of progress in ALS genetics and the subsequent acquisition of insights into the molecular biology of these genes provide grounds for optimism that meaningful therapies for ALS are attainable.

DOI10.1172/JCI71601
Alternate JournalJ. Clin. Invest.
Citation Key10.1172/JCI71601
PubMed ID25932674
PubMed Central IDPMC4463186
Grant ListRC2 NS070342 / NS / NINDS NIH HHS / United States
1RC1NS068391-01 / NS / NINDS NIH HHS / United States
R01 NS088689 / NS / NINDS NIH HHS / United States
R01 NS065847 / NS / NINDS NIH HHS / United States
RC1 NS068391 / NS / NINDS NIH HHS / United States
R01NS050557-05 / NS / NINDS NIH HHS / United States
R01 NS050557 / NS / NINDS NIH HHS / United States
1RC2NS070342-01 / NS / NINDS NIH HHS / United States
R01NS065847-01A1 / NS / NINDS NIH HHS / United States