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LINCing Defective Nuclear-Cytoskeletal Coupling and DYT1 Dystonia

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Abstract

Mechanical forces generated by nuclear-cytoskeletal coupling through the linker of nucleoskeleton and cytoskeleton (LINC) complex, an evolutionarily conserved molecular bridge in the nuclear envelope (NE), are critical for the execution of wholesale nuclear positioning events in migrating and dividing cells, chromosome dynamics during meiosis, and mechanotransduction. LINC complexes consist of outer Klarsicht, ANC-1, and Syne homology (KASH) and inner Sad1, UNC-84 (SUN) nuclear membrane proteins. KASH proteins interact with the cytoskeleton in the cytoplasm and SUN proteins in the perinuclear space of the NE. In the nucleoplasm, SUN proteins interact with A-type nuclear lamins and chromatin-binding proteins. Recent structural insights into the KASH-SUN interaction have generated several questions regarding how LINC complex assembly and function might be regulated within the perinuclear space. Here we discuss potential LINC regulatory mechanisms and focus on the potential role of the ATPases associated with various cellular activities (AAA+) protein, torsinA, as a LINC complex regulator within the NE. We also examine how defects in LINC complex regulation by torsinA may contribute to the pathogenesis of the human neurological movement disorder, DYT1 dystonia.

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Acknowledgments

We thank Drs. Melissa Gardner, David Greenstein, Joachim Mueller, and Meg Titus for helpful discussions. The authors apologize to those whose work we were unable to cite and cover in proper depth due to the limitations of length for this review. Studies in the Luxton Lab are supported by start up funding from the University of Minnesota, a P30 Pilot and Feasibility Grant from the Paul and Sheila Wellstone Muscular Dystrophy Center, and funding from the NIH (R21 NS095109-01, 1R41DA037622, and AR57220). C.A.S. is supported by an NIH training grant (NIH 5T32AR007612-14).

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Cosmo A. Saunders and G.W. Gant Luxton have no conflicts on interest.

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  1. Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis, MN, 55455, USA

    Cosmo A. Saunders & G. W. Gant Luxton

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Correspondence to G. W. Gant Luxton.

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Associate Editor Kris Noel Dahl oversaw the review of this article.

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Saunders, C.A., Luxton, G.W.G. LINCing Defective Nuclear-Cytoskeletal Coupling and DYT1 Dystonia. Cel. Mol. Bioeng. 9, 207–216 (2016). https://doi.org/10.1007/s12195-016-0432-0

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