title: C9ORF72 interaction with cofilin modulates actin dynamics in motor neurons.
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.
authors.affiliation: Institute of Clinical Neurobiology, University Hospital of Wuerzburg, Wuerzburg, Germany.
authors.forename: Rajeeve
authors.initials: R
authors.lastname: Sivadasan
authors.affiliation: Max Planck Institute of Biochemistry, Martinsried, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Hornburg
authors.affiliation: Institute of Clinical Neurobiology, University Hospital of Wuerzburg, Wuerzburg, Germany.
authors.forename: Carsten
authors.identifier: 0000-0002-7883-6479
authors.initials: C
authors.lastname: Drepper
authors.affiliation: Institute of Clinical Neurobiology, University Hospital of Wuerzburg, Wuerzburg, Germany.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Frank
authors.affiliation: Institute of Clinical Neurobiology, University Hospital of Wuerzburg, Wuerzburg, Germany.
authors.forename: Sibylle
authors.initials: S
authors.lastname: Jablonka
authors.affiliation: Institute of Clinical Neurobiology, University Hospital of Wuerzburg, Wuerzburg, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Hansel
authors.affiliation: Department of Neurology, Technische Universität Dresden, Dresden, Germany.
authors.forename: Xenia
authors.initials: X
authors.lastname: Lojewski
authors.affiliation: Center for Regenerative Therapies Dresden (CRTD), Technische Universität Dresden, Dresden, Germany.
authors.forename: Jared
authors.initials: J
authors.lastname: Sterneckert
authors.affiliation: Department of Neurology, Technische Universität Dresden, Dresden, Germany.|Center for Regenerative Therapies Dresden (CRTD), Technische Universität Dresden, Dresden, Germany.|German Center for Neurodegenerative Diseases (DZNE), Dresden, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Hermann
authors.affiliation: Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, UK.
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Shaw
authors.affiliation: Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, UK.
authors.forename: Paul G
authors.initials: PG
authors.lastname: Ince
authors.affiliation: Max Planck Institute of Biochemistry, Martinsried, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Mann
authors.affiliation: Max Planck Institute of Biochemistry, Martinsried, Germany.
authors.forename: Felix
authors.identifier: 0000-0003-1000-7989
authors.initials: F
authors.lastname: Meissner
authors.affiliation: Institute of Clinical Neurobiology, University Hospital of Wuerzburg, Wuerzburg, Germany.
authors.forename: Michael
authors.identifier: 0000-0002-4737-2974
authors.initials: M
authors.lastname: Sendtner
mesh_terms: D051339:Actin Depolymerizing Factors / Q000378:metabolism*; D000199:Actins / Q000378:metabolism*; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism; D000073885:C9orf72 Protein; D042622:DNA Repeat Expansion / Q000235:genetics; D057180:Frontotemporal Dementia / Q000235:genetics / Q000378:metabolism; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics*; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism*; D051379:Mice; D008840:Microfilament Proteins / Q000378:metabolism; D009046:Motor Neurons / Q000378:metabolism*; D011506:Proteins / Q000235:genetics*
chemical_list: D051339:Actin Depolymerizing Factors; D000199:Actins; D000073885:C9orf72 Protein; C568651:C9orf72 protein, human; C000606498:C9orf72 protein, mouse; D020662:Guanine Nucleotide Exchange Factors; D008840:Microfilament Proteins; D011506:Proteins