C9ORF72 interaction with cofilin modulates actin dynamics in motoneurons

ABSTRACT: Intronic hexanucleotide expansions in C9ORF72 are common in ALS and FTLD, 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 motoneurons and found that C9ORF72 is present in a complex with cofilin and other actin binding proteins. Phosphorylation of cofilin is enhanced in C9ORF72 depleted motoneurons, in patient derived lymphoblastoid cells, iPS cell derived motoneurons and post-mortem brain samples from ALS patients. C9ORF72 modulates the activity of the small GTPases Arf6 and Rac1, resulting in enhanced activity of LIMK1/2. This results in reduced axonal actin dynamics in C9ORF72 depleted motoneurons. Dominant negative Arf6 rescues this defect, suggesting that C9ORF72 acts as a modulator of small GTPases in a pathway that regulates axonal actin dynamics.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Permanent Cell Line Cell

DISEASE(S): Amyotrophic Lateral Sclerosis

SUBMITTER: Mario Oroshi  

LAB HEAD: Felix Meissner

PROVIDER: PXD004913 | Pride | 2016-09-30

REPOSITORIES: Pride