LINCing Defective Nuclear-Cytoskeletal Coupling and DYT1 Dystonia

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.