C9ORF72 interaction with cofilin modulates actin dynamics in motor neurons

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

doi:10.1038/nn.4407

C9ORF72 interaction with cofilin modulates actin dynamics in motor neurons

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

63 Citations (Scopus)

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.

Original language	English
Journal	Nature Neuroscience
Volume	19
Issue number	12
Pages (from-to)	1610-1618
Number of pages	9
ISSN	1097-6256
DOIs	https://doi.org/10.1038/nn.4407
Publication status	Published - 1 Dec 2016
Externally published	Yes

Keywords

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

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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.",

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

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AU - Sivadasan, Rajeeve

AU - Hornburg, Daniel

AU - Drepper, Carsten

AU - Frank, Nicolas

AU - Jablonka, Sibylle

AU - Hansel, Anna

AU - Lojewski, Xenia

AU - Sterneckert, Jared

AU - Hermann, Andreas

AU - Shaw, Pamela J

AU - Ince, Paul G

AU - Mann, Matthias

AU - Meissner, Felix

AU - Sendtner, Michael

PY - 2016/12/1

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N2 - 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.

AB - 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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KW - Animals

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KW - Induced Pluripotent Stem Cells

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JF - Nature Neuroscience

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ER -

C9ORF72 interaction with cofilin modulates actin dynamics in motor neurons

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