Nuclear Pore Complex Dysfunction in Dystonia Pathogenesis: Nucleoporins in the Spotlight

Hot Topic article on: Prophet SM, Rampello AJ, Niescier RF, et al. Atypical nuclear envelope condensates linked to neurological disorders reveal nucleoporin-directed chaperone activities. Nat Cell Biol 2022. Advances in genetic profiling have led to the discovery of a number of molecular defects involved in the development of dystonia. Despite the progress in this field, relationships between the associated disease pathways remain difficult to understand, and no consensus on unifying driver molecules has been reached. Dysfunction of torsinA induced by a recurrent mutation in TOR1A has been identified as the first monogenic cause of dystonia, but the pathogenesis of clinical manifestations is still incompletely understood. In an article published in the Nature series, Prophet and colleagues now provide fascinating insights into the roles of nuclear pore complexes (NPCs) and a subset of its components, the phenylalanine-glycine-rich region-containing nucleoporins (FG-NUPs), in the etiology of TOR1A-related dystonia. NPCs are cylindrical channels in the nuclear envelope, controlling bidirectional exchange of biomolecules, and built from about 30 different nucleoporins. The highly conserved group of FGNUPs (NUP98, NUP54, NUP62, and others) line the interior of NPCs, forming a permeability barrier, and thus represent key mediators of nucleocytoplasmic transport. By studying virally derived model proteins tied to nuclear transport, comparative mass spectrometry–based proteomics data, and microscopic ultrastructural changes in torsinA knock-out cell lines and primary mouse neurons, Prophet and colleagues reveal two main mechanisms contributing to cellular pathology in the context of torsinA dysfunction. First, the authors highlight the formation of abnormal “bleb”-like herniations containing nonfunctional FG-NUPs at the nuclear envelope of affected cells, resulting in NPC-biogenesis deficits. Second, they demonstrate that FG-NUP-enriched condensates in “blebs” result in sequestration of protein quality-control network components such as HSP40/HSP70 chaperones, triggering a cascade of proteotoxic stress. Both pathological effects observed in relation to mutant torsinA implicate FG-NUP perturbation in the genesis of early-onset dystonic movements, most likely via mechanisms of impaired nucleocytoplasmic shuttling, compromised intracellular proteostasis, or a combination thereof. Prophet and colleagues also propose that the transient nature of “blebs” with enrichment of FG-NUPs can explain the window of vulnerability associated with penetrance of TOR1Arelated dystonia (developmental period until about 30 years), depending on how effectively cells can cope with nucleartransport defects and proteotoxicity. In support of a wider role for FG-NUPs in dystonia pathogenesis, a particular member of this protein family has been most recently linked to a new hereditary form of the disease: bi-allelic variants of NUP54 were shown to underlie earlyonset dystonia with striatal lesions; affected individuals presented generalized progressive dystonia, whereas their cells exhibited profound reductions in NUP54 and other FG-NUP levels indicative of NPC dysfunction. The cumulative evidence, considered together with the previously established association between dystonia and further FGNUPs such as NUP62, suggests that these proteins should be added to the list of molecules that may have broader mechanistic implications across different dystonia subtypes and patient groups. A better understanding of the genetic and molecular basis of FG-NUP involvement in dystonia pathophysiology may help in developing more efficacious treatments.