Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.10.14.338566v1?rss=1

Authors: Shiota, T., Nagata, R., Kikuchi, S., Nanaura, H., Matsubayashi, M., Nakanishi, M., Kobashigawa, S., Nagayama, K., Sugie, K., Yamashiro, Y., Mori, E.

Abstract:

Amyotrophic lateral sclerosis (ALS) is an irreversible neurodegenerative disease caused by the degeneration of motor neurons, and cytoskeletal instability is considered to be involved in neurodegeneration. A hexanucleotide repeat expansion of the C9orf72, one of the most common causes of familial ALS, produces toxic proline:arginine (PR) poly-dipeptides. PR poly-dipeptides binds polymeric forms of low complexity sequences and intracellular puncta, thereby altering intermediate filaments (IFs). However, how PR poly-dipeptides affect the cytoskeleton, including IFs, microtubules and actin filaments, remains unknown. Here we performed a synthetic PR poly-dipeptide treatment on mammalian cells and investigated how it affects morphology of cytoskeleton and cell behaviors. We observed that PR poly-dipeptide treatment induce the degradation of vimentin bundles at perinucleus and dissociation of {beta}-tubulin network. PR poly-dipeptides also lead to alteration of actin filaments toward to cell contours and strength cortical actin filaments via activation of ERM (ezrin/radixin/moesin) proteins. In addition, we found that PR poly-dipeptides promote phosphorylation of paxillin and recruitment of vinculin on focal adhesions, which lead to maturation of focal adhesions. Finally, we evaluated the effects of PR poly-dipeptides on mechanical property and stress response. Interestingly, treatment of PR poly-dipeptides increased the elasticity of the cell surface, leading to maladaptive response to cyclic stretch. These results suggest that PR poly-dipeptides cause mechanically sensitive structural reorganization and disrupt the cytoskeleton architecture.

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