Editors' ChoiceAmyotrophic Lateral Sclerosis

Elucidating the role of C9orf72 mutations in ALS

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Science Translational Medicine  24 Jun 2015:
Vol. 7, Issue 293, pp. 293ec106
DOI: 10.1126/scitranslmed.aac7161

The most common cause of familial amyotrophic lateral sclerosis (ALS) is a hexanucleotide repeat expansion on chromosome 9 open reading frame 72 (C9orf72). Proposed pathological mechanisms include sequestration of RNA-binding proteins and toxic gain or loss of function. Evidence supporting a loss-of-function for C9orf72 includes decreased mRNA in cells from ALS patients, decreased C9orf72 protein in postmortem tissue, and knockdown experiments in simple animal systems. In a new work, Koppers and colleagues use a conditional mouse knockout model to show that loss-of function of C9orf72 does not cause defects in motor function or decrease survival.

Koppers et al. created a C9orf72 knockout mouse model in which C9orf72 could be selectively removed from neurons and glial cells. They studied changes in motor neurons and neuromuscular integrity, pathological hallmarks of ALS including gliosis and TDP43 mislocalization, and motor neuron function and survival. They first created a C9orf72-expressing mouse where C9orf72 protein was detected both in adult motor neurons and glial cells in the brain and spinal cord, and also in embryonic and postnatal neurons. This supported a role for C9orf72 in embryonic and postnatal development. To circumvent problems with embryonic lethality, the authors then created a conditional knockout mouse using the Cre-loxP system. Although knockdown of C9orf72 caused decreased body weight, it did not result in decreased motor neuron size or number, did not result in pathological hallmarks of ALS or decreased motor performance, and did not alter animal survival.

The authors conclude that loss-of-function of C9orf72 in ALS is insufficient to cause disease in mice. A better understanding of how C9orf72 mutations cause ALS could lead to strategies for disease-directed therapies to treat ALS. In addition, they conclude that therapeutic approaches using antisense oligonucleotides directed at the C9orf72 repeat expansion that lower C9orf72 expression could still benefit ALS patients.

M. Koppers et al., C9orf72 ablation in mice does not cause motor neuron degeneration or motor deficits. Ann. Neurol. 10.1002/ana.24453 (2015). [Abstract]

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