2. Academic Validation
  3. C9ORF72 interaction with cofilin modulates actin dynamics in motor neurons

C9ORF72 interaction with cofilin modulates actin dynamics in motor neurons

  • Nat Neurosci. 2016 Dec;19(12):1610-1618. doi: 10.1038/nn.4407.
Rajeeve Sivadasan 1,  Daniel Hornburg 2,  Carsten Drepper 1,  Nicolas Frank 1,  Sibylle Jablonka 1,  Anna Hansel 1,  Xenia Lojewski 3,  Jared Sterneckert 4,  Andreas Hermann 3 4 5,  Pamela J Shaw 6,  Paul G Ince 6,  Matthias Mann 2,  Felix Meissner 2,  Michael Sendtner 1
Affiliations

Affiliations

  • 1 Institute of Clinical Neurobiology, University Hospital of Wuerzburg, Wuerzburg, Germany.
  • 2 Max Planck Institute of Biochemistry, Martinsried, Germany.
  • 3 Department of Neurology, Technische Universität Dresden, Dresden, Germany.
  • 4 Center for Regenerative Therapies Dresden (CRTD), Technische Universität Dresden, Dresden, Germany.
  • 5 German Center for Neurodegenerative Diseases (DZNE), Dresden, Germany.
  • 6 Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, UK.
PMID: 27723745 DOI: 10.1038/nn.4407
Abstract

Intronic hexanucleotide expansions in C9ORF72 are common in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia, but it is unknown whether loss of function, toxicity by the expanded RNA or dipeptides from non-ATG-initiated translation are responsible for the pathophysiology. We determined the interactome of C9ORF72 in motor neurons and found that C9ORF72 was present in a complex with cofilin and Other actin binding proteins. Phosphorylation of cofilin was enhanced in C9ORF72-depleted motor neurons, in patient-derived lymphoblastoid cells, induced pluripotent stem cell-derived motor neurons and post-mortem brain samples from ALS patients. C9ORF72 modulates the activity of the small GTPases Arf6 and Rac1, resulting in enhanced activity of LIM-kinases 1 and 2 (LIMK1/2). This results in reduced axonal actin dynamics in C9ORF72-depleted motor neurons. Dominant negative Arf6 rescues this defect, suggesting that C9ORF72 acts as a modulator of small GTPases in a pathway that regulates axonal actin dynamics.

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