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  C9ORF72 interaction with cofilin modulates actin dynamics in motor neurons

Sivadasan, R., Hornburg, D., Drepper, C., Frank, N., Jablonka, S., Hansel, A., et al. (2016). C9ORF72 interaction with cofilin modulates actin dynamics in motor neurons. Nature Neuroscience, 19(12), 1610-1618. doi:10.1038/nn.4407.

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 Creators:
Sivadasan, Rajeeve1, Author
Hornburg, Daniel2, Author              
Drepper, Carsten1, Author
Frank, Nicolas1, Author
Jablonka, Sibylle1, Author
Hansel, Anna1, Author
Lojewski, Xenia1, Author
Sterneckert, Jared1, Author
Hermann, Andreas1, Author
Shaw, Pamela J.1, Author
Ince, Paul G.1, Author
Mann, Matthias2, Author              
Meissner, Felix3, Author              
Sendtner, Michael1, Author
Affiliations:
1external, ou_persistent22              
2Mann, Matthias / Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565159              
3Meissner, Felix / Experimental Systems Immunology, Max Planck Institute of Biochemistry, Max Planck Society, ou_2149678              

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Free keywords: DIPEPTIDE-REPEAT PROTEINS; FRONTOTEMPORAL DEMENTIA; DOWNSTREAM ACTIVATION; HEXANUCLEOTIDE REPEAT; LATERAL SCLEROSIS; GGGGCC REPEAT; RNA FOCI; ARF6; ALS; EXPANSIONNeurosciences & Neurology;
 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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Language(s): eng - English
 Dates: 2016-10-102016
 Publication Status: Published in print
 Pages: 9
 Publishing info: -
 Table of Contents: -
 Rev. Type: -
 Identifiers: ISI: 000389011900020
DOI: 10.1038/nn.4407
 Degree: -

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Title: Nature Neuroscience
  Other : Nat. Neurosci.
Source Genre: Journal
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Publ. Info: New York, NY : Nature America Inc.
Pages: - Volume / Issue: 19 (12) Sequence Number: - Start / End Page: 1610 - 1618 Identifier: ISSN: 1097-6256
CoNE: https://pure.mpg.de/cone/journals/resource/954925610931