C9ORF72 interaction with cofilin modulates actin dynamics in motor neurons

• Published in: Nature neuroscience Vol. 19; no. 12; pp. 1610 - 1618
• Main Authors: Sivadasan, Rajeeve, Hornburg, Daniel, Drepper, Carsten, Frank, Nicolas, Jablonka, Sibylle, Hansel, Anna, Lojewski, Xenia, Sterneckert, Jared, Hermann, Andreas, Shaw, Pamela J, Ince, Paul G, Mann, Matthias, Meissner, Felix, Sendtner, Michael
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01-12-2016; Nature Publishing Group
• Subjects: 13/1; 13/100; 13/109; 14; 14/63; 631/378/1689/364; 631/378/340; 82; 82/58; Actin Depolymerizing Factors - metabolism; Actins - metabolism; Alzheimer's disease; Amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis - genetics; Amyotrophic Lateral Sclerosis - metabolism; Analysis; Animal Genetics and Genomics; Animals; Behavioral Sciences; Biological Techniques; Biomedicine; Brain - metabolism; C9orf72 Protein; Child & adolescent psychiatry; Dementia; Disease; DNA Repeat Expansion - genetics; Frontotemporal Dementia - genetics; Frontotemporal Dementia - metabolism; Genetic aspects; Genomics; Guanine Nucleotide Exchange Factors - genetics; Humans; Hypotheses; Induced Pluripotent Stem Cells - metabolism; Kinases; Metabolism; Mice; Microfilament Proteins - metabolism; Motor Neurons - metabolism; Neurobiology; Neurodegeneration; Neurons; Neurosciences; Pathophysiology; Patients; Phosphorylation; Physiological aspects; Protein binding; Proteins; Proteins - genetics; Risk factors; Toxicity; Germany
• ISSN: 1097-6256; 1546-1726
• DOI: 10.1038/nn.4407

In this study, Sivadasan
et al
. show that the interactome of the C9ORF72 protein contains cofilin and other actin-binding proteins. They also demonstrate that actin dynamics are reduced in patient-derived motor neurons and tissues with ALS-related intronic expansion of the C9ORF72 gene, leading to altered axon growth and growth cone dynamics.
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.