Sporadic and hereditary amyotrophic lateral sclerosis (ALS)

Senda Ajroud-Driss; Teepu Siddique

doi:10.1016/j.bbadis.2014.08.010

Sporadic and hereditary amyotrophic lateral sclerosis (ALS)

Biochim Biophys Acta. 2015 Apr;1852(4):679-84. doi: 10.1016/j.bbadis.2014.08.010. Epub 2014 Sep 1.

Authors

Senda Ajroud-Driss¹, Teepu Siddique²

Affiliations

¹ Division of Neuromuscular Medicine, The Ken and Ruth Davee Department of Neurology and Clinical Neurosciences, Feinberg School of Medicine Northwestern University, Chicago, IL 60611, USA. Electronic address: s-ajroud@northwestern.edu.
² Division of Neuromuscular Medicine, The Ken and Ruth Davee Department of Neurology and Clinical Neurosciences, Feinberg School of Medicine Northwestern University, Chicago, IL 60611, USA; Department of Cell and Molecular Biology, Feinberg School of Medicine Northwestern University, Chicago, IL, USA.

PMID: 25193032
DOI: 10.1016/j.bbadis.2014.08.010

Abstract

Genetic discoveries in ALS have a significant impact on deciphering molecular mechanisms of motor neuron degeneration. The identification of SOD1 as the first genetic cause of ALS led to the engineering of the SOD1 mouse, the backbone of ALS research, and set the stage for future genetic breakthroughs. In addition, careful analysis of ALS pathology added valuable pieces to the ALS puzzle. From this joint effort, major pathogenic pathways emerged. Whereas the study of TDP43, FUS and C9ORF72 pointed to the possible involvement of RNA biology in motor neuron survival, recent work on P62 and UBQLN2 refocused research on protein degradation pathways. Despite all these efforts, the etiology of most cases of sporadic ALS remains elusive. Newly acquired genomic tools now allow the identification of genetic and epigenetic factors that can either increase ALS risk or modulate disease phenotype. These developments will certainly allow for better disease modeling to identify novel therapeutic targets for ALS. This article is part of a Special Issue entitled: Neuromuscular Diseases: Pathology and Molecular Pathogenesis.

Keywords: Familial ALS; Paradigm shift; Pathogenesis; Sporadic ALS.

Publication types

Review

MeSH terms

Adaptor Proteins, Signal Transducing
Adaptor Proteins, Vesicular Transport / genetics
Adaptor Proteins, Vesicular Transport / metabolism
Amyotrophic Lateral Sclerosis* / genetics
Amyotrophic Lateral Sclerosis* / metabolism
Amyotrophic Lateral Sclerosis* / pathology
Animals
Autophagy-Related Proteins
C9orf72 Protein
Cell Cycle Proteins / genetics
Cell Cycle Proteins / metabolism
Cell Survival
DNA-Binding Proteins / genetics
DNA-Binding Proteins / metabolism
Epigenesis, Genetic
Genetic Diseases, Inborn* / genetics
Genetic Diseases, Inborn* / metabolism
Genetic Diseases, Inborn* / pathology
Humans
Mice
Motor Neurons* / metabolism
Motor Neurons* / pathology
Proteins / genetics
Proteins / metabolism
RNA-Binding Protein FUS / genetics
RNA-Binding Protein FUS / metabolism
RNA-Binding Proteins / genetics
RNA-Binding Proteins / metabolism
Superoxide Dismutase / genetics
Superoxide Dismutase / metabolism
Superoxide Dismutase-1
Ubiquitins / genetics
Ubiquitins / metabolism

Substances

Adaptor Proteins, Signal Transducing
Adaptor Proteins, Vesicular Transport
Autophagy-Related Proteins
C9orf72 Protein
C9orf72 protein, human
Cell Cycle Proteins
DNA-Binding Proteins
FUS protein, human
FUS protein, mouse
P62 protein, human
Proteins
RNA-Binding Protein FUS
RNA-Binding Proteins
SOD1 protein, human
TARDBP protein, human
TDP-43 protein, mouse
UBQLN2 protein, human
UBQLN2 protein, mouse
Ubiquitins
Sod1 protein, mouse
Superoxide Dismutase
Superoxide Dismutase-1

Supplementary concepts

Amyotrophic lateral sclerosis 1