University of Massachusetts Medical School Faculty Publications

Title

Amyotrophic lateral sclerosis: Problems and prospects

UMMS Affiliation

Department of Neurology

Publication Date

9-2013

Document Type

Article

Subjects

Amyotrophic Lateral Sclerosis; Genetic Testing; Genetic Therapy; Humans; Motor Neurons; Mutation; RNA-Binding Protein FUS; Superoxide Dismutase

Disciplines

Medical Neurobiology | Neurology | Neuroscience and Neurobiology

Abstract

Amyotrophic lateral sclerosis (ALS) is a lethal degenerative disorder of motoneurons, which may occur concurrently with frontotemporal dementia. Genetic analyses of the approximately 10% of ALS cases that are dominantly inherited provide insight into ALS pathobiology. Two broad themes are evident. One, prompted by investigations of the SOD1 gene, is that conformational instability of proteins triggers downstream neurotoxic processes. The second, from studies of the TDP43, FUS, and C9orf72 genes, is that perturbations of RNA processing can be highly adverse in motoneurons. Several investigations support the concept that non-neuronal cells (microglia, astroglia, oligodendroglia) participate in the degenerative process in ALS. Recent data also emphasize the importance of molecular events in the axon and distal motoneuron terminals. Only 1 compound, riluzole, is approved by the US Food and Drug Administration for ALS; several therapies are in clinical trials, including 2 mesenchymal stem cell trials. The challenges and unmet needs in ALS emphasize the importance of new research directions: high-throughput sequencing of large DNA sets of familial and sporadic ALS, which will define scores of candidate ALS genes and pathways and facilitate studies of epistasis and epigenetics; infrastructures for candidate gene validation, including in vitro and in vivo modeling; valid biomarkers that elucidate causative molecular events and accelerate clinical trials; and in the long term, methods to identify environmental toxins. The unprecedented intensity of research in ALS and the advent of extraordinary technologies (rapid, inexpensive DNA sequencing; stem cell production from skin-derived fibroblasts; silencing of miscreant mutant genes) bode well for discovery of innovative ALS therapies.

Rights and Permissions

Citation: Ann Neurol. 2013 Sep;74(3):309-16. doi: 10.1002/ana.24012. Link to article on publisher's site

Related Resources

Link to Article in PubMed

Journal/Book/Conference Title

Annals of neurology

PubMed ID

24038380