C9ORF72 interaction with cofilin modulates actin dynamics in motor neurons

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

doi:10.1038/nn.4407

Cited by 140 publications

(148 citation statements)

References 64 publications

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“…Thus, alteration of cofilin‐1 signalling and actin dynamics appears tightly correlated to neurodegeneration. Importantly, as we have found here in SOD1‐ALS mice, increased cofilin‐1 phosphorylation was observed in post‐mortem samples from ALS patients (Sivadasan et al , ). In addition, genetic links between ALS and alteration of actin dynamics also exist with mutations in the gene encoding the actin‐binding protein profilin 1, a protein with dual function on actin dynamics, causing familial ALS (Wu et al , ).…”

Section: Discussionsupporting

confidence: 83%

“…These repeats are translated in di‐peptide repeat proteins which also spread like prions (Westergard et al , ). Intriguingly, C9orf72 was found to interact with cofilin‐1 and to increase cofilin‐1 phosphorylation through LIMK1/2 (Sivadasan et al , ). Our findings provide a mechanistic starting point to evaluate the interplay between cofilin‐1, actin dynamics and the spread of aggregates.…”

Section: Discussionmentioning

confidence: 99%

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Prion‐like protein aggregates exploit the RHO GTPase to cofilin‐1 signaling pathway to enter cells

et al. 2018

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Protein aggregation is a hallmark of diverse neurodegenerative diseases. Multiple lines of evidence have revealed that protein aggregates can penetrate inside cells and spread like prions. How such aggregates enter cells remains elusive. Through a focused siRNA screen targeting genes involved in membrane trafficking, we discovered that mutant SOD1 aggregates, like viruses, exploit cofilin-1 to remodel cortical actin and enter cells. Upstream of cofilin-1, signalling from the RHO GTPase and the ROCK1 and LIMK1 kinases controls cofilin-1 activity to remodel actin and modulate aggregate entry. In the spinal cord of symptomatic SOD1 transgenic mice, cofilin-1 phosphorylation is increased and actin dynamics altered. Importantly, the RHO to cofilin-1 signalling pathway also modulates entry of tau and α-synuclein aggregates. Our results identify a common host cell signalling pathway that diverse protein aggregates exploit to remodel actin and enter cells.

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Section: Discussionsupporting

confidence: 83%

Section: Discussionmentioning

confidence: 99%

Prion‐like protein aggregates exploit the RHO GTPase to cofilin‐1 signaling pathway to enter cells

et al. 2018

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“…Recent studies reported that mutations of profilin 1 (PFN1), an actin binding protein, affect cytoskeletal dynamics and aggregation of TDP-4358. Moreover, ALS/FTD-linked C9ORF72 expansion has been shown to dysregulate actin dynamics in motor neurons59. Our study showed that Nd1-L expression rescued neurite shortening enhanced further by loss of PRMT1 in FUS-R521C expressing neurons, thus supporting that improper regulation of actin cytoskeleton might contribute to cellular pathogenesis associated with ALS.…”

Section: Discussionsupporting

confidence: 76%

Sequestration of PRMT1 and Nd1-L mRNA into ALS-linked FUS mutant R521C-positive aggregates contributes to neurite degeneration upon oxidative stress

Jun

Ryu

Jun

et al. 2017

Sci Rep

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Mutations in fused in sarcoma (FUS), a DNA/RNA binding protein, are associated with familial amyotrophic lateral sclerosis (ALS). However, little is known about how ALS-causing mutations alter protein-protein and protein-RNA complexes and contribute to neurodegeneration. In this study, we identified protein arginine methyltransferase 1 (PRMT1) as a protein that more avidly associates with ALS-linked FUS-R521C than with FUS-WT (wild type) or FUS-P525L using co-immunoprecipitation and LC-MS analysis. Abnormal association between FUS-R521C and PRMT1 requires RNA, but not methyltransferase activity. PRMT1 was sequestered into cytosolic FUS-R521C-positive stress granule aggregates. Overexpression of PRMT1 rescued neurite degeneration caused by FUS-R521C upon oxidative stress, while loss of PRMT1 further accumulated FUS-positive aggregates and enhanced neurite degeneration. Furthermore, the mRNA of Nd1-L, an actin-stabilizing protein, was sequestered into the FUS-R521C/PRMT1 complex. Nd1-L overexpression rescued neurite shortening caused by FUS-R521C upon oxidative stress, while loss of Nd1-L further exacerbated neurite shortening. Altogether, these data suggest that the abnormal stable complex of FUS-R521C/PRMT1/Nd1-L mRNA could contribute to neurodegeneration upon oxidative stress. Overall, our study provides a novel pathogenic mechanism of the FUS mutation associated with abnormal protein-RNA complexes upon oxidative stress in ALS and provides insight into possible therapeutic targets for this pathology.

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“…Apoptotic MNs also display defects in soma size and neurite length (Chen et al., 2014, Kiskinis et al., 2014). Although neurite defects have not been observed in C9ORF72 mutant MNs, interference with actin dynamics via interaction of C9ORF72 with cofilin can be expected to result in axonal defects (Sivadasan et al., 2016). An activated p53 response was observed in C9ORF72 mutant MNs (Lopez-Gonzalez et al., 2016) similar to our observation of an increased nuclear p53 in SOD1 MNs compared with the control and isogenic corrected MNs.…”

Section: Discussionmentioning

confidence: 99%

Genetic Correction of SOD1 Mutant iPSCs Reveals ERK and JNK Activated AP1 as a Driver of Neurodegeneration in Amyotrophic Lateral Sclerosis

et al. 2017

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SummaryAlthough mutations in several genes with diverse functions have been known to cause amyotrophic lateral sclerosis (ALS), it is unknown to what extent causal mutations impinge on common pathways that drive motor neuron (MN)-specific neurodegeneration. In this study, we combined induced pluripotent stem cells-based disease modeling with genome engineering and deep RNA sequencing to identify pathways dysregulated by mutant SOD1 in human MNs. Gene expression profiling and pathway analysis followed by pharmacological screening identified activated ERK and JNK signaling as key drivers of neurodegeneration in mutant SOD1 MNs. The AP1 complex member JUN, an ERK/JNK downstream target, was observed to be highly expressed in MNs compared with non-MNs, providing a mechanistic insight into the specific degeneration of MNs. Importantly, investigations of mutant FUS MNs identified activated p38 and ERK, indicating that network perturbations induced by ALS-causing mutations converge partly on a few specific pathways that are drug responsive and provide immense therapeutic potential.

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C9ORF72 interaction with cofilin modulates actin dynamics in motor neurons

Cited by 140 publications

References 64 publications

Prion‐like protein aggregates exploit the RHO GTPase to cofilin‐1 signaling pathway to enter cells

Prion‐like protein aggregates exploit the RHO GTPase to cofilin‐1 signaling pathway to enter cells

Sequestration of PRMT1 and Nd1-L mRNA into ALS-linked FUS mutant R521C-positive aggregates contributes to neurite degeneration upon oxidative stress

Genetic Correction of SOD1 Mutant iPSCs Reveals ERK and JNK Activated AP1 as a Driver of Neurodegeneration in Amyotrophic Lateral Sclerosis

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