TorsinA dysfunction causes persistent neuronal nuclear pore defects

• Published in: Human molecular genetics Vol. 27; no. 3; pp. 407 - 420
• Main Authors: Pappas, Samuel S, Liang, Chun-Chi, Kim, Sumin, Rivera, CheyAnne O, Dauer, William T
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 01.02.2018
• Subjects: Animals; Cells, Cultured; Dystonic Disorders - metabolism; Dystonic Disorders - pathology; Female; Genotype; Immunohistochemistry; Male; Mice; Mice, Knockout; Microtubule-Associated Proteins - genetics; Microtubule-Associated Proteins - metabolism; Molecular Chaperones - genetics; Molecular Chaperones - metabolism; Nuclear Envelope - genetics; Nuclear Envelope - metabolism; Nuclear Pore - metabolism; Nuclear Pore - pathology
• ISSN: 0964-6906; 1460-2083
• DOI: 10.1093/hmg/ddx405

Abstract A critical challenge to deciphering the pathophysiology of neurodevelopmental disease is identifying which of the myriad abnormalities that emerge during CNS maturation persist to contribute to long-term brain dysfunction. Childhood-onset dystonia caused by a loss-of-function mutation in the AAA+ protein torsinA exemplifies this challenge. Neurons lacking torsinA develop transient nuclear envelope (NE) malformations during CNS maturation, but no NE defects are described in mature torsinA null neurons. We find that during postnatal CNS maturation torsinA null neurons develop mislocalized and dysfunctional nuclear pore complexes (NPC) that lack NUP358, normally added late in NPC biogenesis. SUN1, a torsinA-related molecule implicated in interphase NPC biogenesis, also exhibits localization abnormalities. Whereas SUN1 and associated nuclear membrane abnormalities resolve in juvenile mice, NPC defects persist into adulthood. These findings support a role for torsinA function in NPC biogenesis during neuronal maturation and implicate altered NPC function in dystonia pathophysiology.