C9ORF72 interaction with cofilin modulates actin dynamics in motor neurons

Research output: Contribution to journalJournal articleResearchpeer-review

Rajeeve Sivadasan, Daniel Hornburg, Carsten Drepper, Nicolas Frank, Sibylle Jablonka, Anna Hansel, Xenia Lojewski, Jared Sterneckert, Andreas Hermann, Pamela J Shaw, Paul G Ince, Matthias Mann, Felix Meissner, Michael Sendtner

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.

Original languageEnglish
JournalNature Neuroscience
Volume19
Issue number12
Pages (from-to)1610-1618
Number of pages9
ISSN1097-6256
DOIs
Publication statusPublished - Dec 2016
Externally publishedYes

    Research areas

  • Actin Depolymerizing Factors, Actins, Amyotrophic Lateral Sclerosis, Animals, Brain, DNA Repeat Expansion, Frontotemporal Dementia, Guanine Nucleotide Exchange Factors, Humans, Induced Pluripotent Stem Cells, Mice, Microfilament Proteins, Motor Neurons, Proteins, Journal Article

ID: 184324278