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- W2903058765 abstract "Abstract DYT1 dystonia is a neurological movement disorder that is caused by a loss-of-function mutation in the DYT1 / TOR1A gene, which encodes torsinA, the luminal ATPase-associated (AAA+) protein. TorsinA is required for the assembly of functional linker of nucleoskeleton and cytoskeleton (LINC) complexes, and consequently the mechanical integration of the nucleus and the cytoskeleton. Despite the potential implications of altered mechanobiology in dystonia pathogenesis, the role of torsinA in regulating cellular mechanical phenotype, or mechanotype, in DYT1 dystonia remains unknown. Here, we define the mechanotype of mouse fibroblasts lacking functional torsinA as well as human fibroblasts isolated from DYT1 dystonia patients. We find that the deletion of torsinA or the expression of torsinA containing the DYT1 dystonia-causing ΔE302/303 (ΔE) mutation results in a more deformable cellular mechanotype. We observe a similar increased deformability of mouse fibroblasts that lack lamina-associated polypeptide 1 (LAP1), which interacts with and stimulates the ATPase activity of torsinA in vitro ; as well as with depletion of the LINC complex proteins, Sad1/UNC-84 (SUN)1 and SUN2, lamin A/C, or lamin B1. Moreover, we report that DYT1 dystonia patient-derived fibroblasts are more compliant than fibroblasts isolated from unafflicted individuals. DYT1 fibroblasts also exhibit increased nuclear strain and decreased viability following mechanical stretch. Taken together, our results support a model where the physical connectivity between the cytoskeleton and nucleus contributes to cellular mechanotype. These findings establish the foundation for future mechanistic studies to understand how altered cellular mechanotype may contribute to DYT1 dystonia pathogenesis; this may be particularly relevant in the context of how neurons sense and respond to mechanical forces during traumatic brain injury, which is known to be a major cause of acquired dystonia." @default.
- W2903058765 created "2018-12-11" @default.
- W2903058765 creator A5005772693 @default.
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- W2903058765 creator A5056906710 @default.
- W2903058765 creator A5068606823 @default.
- W2903058765 creator A5085755071 @default.
- W2903058765 date "2018-11-28" @default.
- W2903058765 modified "2023-09-28" @default.
- W2903058765 title "DYT1 dystonia patient-derived fibroblasts have increased deformability and susceptibility to damage by mechanical forces" @default.
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