Pathogenic aggregates alter actin organization and cellular viscosity resulting in stalled clathrin mediated endocytosis
Singh, S. B.; Rajput, S. S.; Sharma, A.; Ananthanarayanan, V.; Nandi, A.; Patil, S. P. V.; majumdar, a.; Subramanyam, D.
10.1101/2023.07.10.548473 bioRxivShow abstract
Protein aggregation is a common underlying feature of neurodegenerative disorders. Cells expressing neurodegeneration-associated mutant proteins show altered uptake of ligands, suggestive of impaired endocytosis, in a manner as yet unknown. Using live cell imaging, we show that clathrin-mediated endocytosis (CME) is affected due to altered actin cytoskeletal organization in the presence of Huntingtin aggregates. Additionally, we find that cells containing Huntingtin aggregates are stiffer and less viscous than their wild-type counterparts due to altered actin conformation, and not merely due to the physical presence of aggregate(s). We further demonstrate that CME and cellular viscosity can be rescued by overexpressing Hip1, Arp2/3 or transient LatrunculinA treatment. Examination of other pathogenic aggregates revealed that only a subset of these display defective CME, along with altered actin organization and increased stiffness. Together, our results point to an intimate connection between functional CME, actin organization and cellular stiffness in the context of neurodegeneration.
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