Pathogenic commonalities between spinal muscular atrophy and amyotrophic lateral sclerosis: Converging roads to therapeutic development.
- Bowerman M School of Medicine, Keele University, Staffordshire, United Kingdom; Institute for Science and Technology in Medicine, Stoke-on-Trent, United Kingdom; Wolfson Centre for Inherited Neuromuscular Disease, RJAH Orthopaedic Hospital, Oswestry, United Kingdom.
- Murray LM Euan McDonald Centre for Motor Neuron Disease Research and Centre for Integrative Physiology, University of Edinburgh, Edinburgh, United Kingdom.
- Scamps F The Institute for Neurosciences of Montpellier, Inserm UMR1051, Univ Montpellier, Saint Eloi Hospital, Montpellier, France.
- Schneider BL Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
- Kothary R Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Canada; Departments of Medicine and Cellular and Molecular Medicine, University of Ottawa, Ottawa, Canada.
- Raoul C The Institute for Neurosciences of Montpellier, Inserm UMR1051, Univ Montpellier, Saint Eloi Hospital, Montpellier, France. Electronic address: cedric.raoul@inserm.fr.
- 2018-01-10
Published in:
- European journal of medical genetics. - 2018
Amyotrophic Lateral Sclerosis
Animals
C9orf72 Protein
DNA-Binding Proteins
Humans
Mice
Motor Neurons
Muscular Atrophy, Spinal
RNA-Binding Protein FUS
Superoxide Dismutase-1
Survival of Motor Neuron 1 Protein
English
Spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS) are the two most common motoneuron disorders, which share typical pathological hallmarks while remaining genetically distinct. Indeed, SMA is caused by deletions or mutations in the survival motor neuron 1 (SMN1) gene whilst ALS, albeit being mostly sporadic, can also be caused by mutations within genes, including superoxide dismutase 1 (SOD1), Fused in Sarcoma (FUS), TAR DNA-binding protein 43 (TDP-43) and chromosome 9 open reading frame 72 (C9ORF72). However, it has come to light that these two diseases may be more interlinked than previously thought. Indeed, it has recently been found that FUS directly interacts with an Smn-containing complex, mutant SOD1 perturbs Smn localization, Smn depletion aggravates disease progression of ALS mice, overexpression of SMN in ALS mice significantly improves their phenotype and lifespan, and duplications of SMN1 have been linked to sporadic ALS. Beyond genetic interactions, accumulating evidence further suggests that both diseases share common pathological identities such as intrinsic muscle defects, neuroinflammation, immune organ dysfunction, metabolic perturbations, defects in neuron excitability and selective motoneuron vulnerability. Identifying common molecular effectors that mediate shared pathologies in SMA and ALS would allow for the development of therapeutic strategies and targeted gene therapies that could potentially alleviate symptoms and be equally beneficial in both disorders. In the present review, we will examine our current knowledge of pathogenic commonalities between SMA and ALS, and discuss how furthering this understanding can lead to the establishment of novel therapeutic approaches with wide-reaching impact on multiple motoneuron diseases.
- Language
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- English
- Open access status
- green
- Identifiers
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- DOI 10.1016/j.ejmg.2017.12.001
- PMID 29313812
- Persistent URL
- https://folia.unifr.ch/global/documents/204507
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