DYT1 dystonia is a neurological movement disorder that is caused by a loss-of-function mutation in the DYT1/TOR1A gene, which encodes torsinA, a conserved luminal ATPases-associated with various cellular activities (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 deformability 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 more deformable cells. 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 the absence of the LINC complex proteins, Sad1/UNC-84 1 (SUN1) and SUN2, lamin A/C, or lamin B1. Consistent with these findings, we also determine that DYT1 dystonia patient-derived fibroblasts are more compliant than fibroblasts isolated from unafflicted individuals. DYT1 dystonia patient-derived fibroblasts also exhibit increased nuclear strain and decreased viability following mechanical stretch. Taken together, our results establish the foundation for future mechanistic studies of the role of cellular mechanotype and LINC-dependent nuclear-cytoskeletal coupling in regulating cell survival following exposure to mechanical stresses.
Bibliographical noteFunding Information:
This work was supported by the NIH (R01 GM129374-01 to GL, AR007612 to CS, RO1 AG047192 to LF, and 1P01HL146358-01 and R35 HL139725 to SY) and the Farber Family Fund (to NG).
Copyright © 2019 Gill, Ly, Kim, Saunders, Fong, Young, Luxton and Rowat. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
- Cell mechanical properties
- LINC complex
- Nuclear envelope