Neuronal Nuclear Membrane Budding Occurs during a Developmental Window Modulated by Torsin Paralogs

Abstract

SUMMARY DYT1 dystonia is a neurodevelopmental disease that manifests during a discrete period of childhood. The disease is caused by impaired function of torsinA, a protein linked to nuclear membrane budding. The relationship of NE budding to neural development and CNS function is unclear, however, obscuring its potential role in dystonia pathogenesis. We find NE budding begins and resolves during a discrete neurodevelopmental window in torsinA null neurons in vivo. The developmental resolution of NE budding corresponds to increased torsinB protein, while ablating torsinB from torsinA null neurons prevents budding resolution and causes lethal neural dysfunction. Developmental changes in torsinB also correlate with NE bud formation in differentiating DYT1 embryonic stem cells, and overexpression of torsinA or torsinB rescues NE bud formation in this system. These findings identify a torsinA neurodevelopmental window that is essential for normal CNS function, and have important implications for dystonia pathogenesis and therapeutics.

Dissecting Torsin/cofactor function at the nuclear envelope: a genetic study

“…When apparently normal TorA KO murine embryonic fibroblasts (MEFs) were treated with short hairpin RNA against TorB, NE blebbing was observed in these cells, suggesting functional redundancy between the two Torsins (Kim et al ., 2010). Consistent with this idea, NE blebbing in TorA KO mice is confined to a specific neurodevelopmental window, and the disappearance of blebs correlates with increased expression of TorB (Tanabe et al ., 2016). Similar NE abnormalities have also been reported in Drosophila melanogaster (Jokhi et al ., 2013) and Caenorhabditis elegans (VanGompel et al ., 2015) upon manipulation of the respective Torsin variants in these organisms, suggesting that Torsin function at the NE is conserved.…”

Functional Genomic Analyses of Mendelian and Sporadic Disease Identify Impaired eIF2α Signaling as a Generalizable Mechanism for Dystonia

“…Compensation by the homologous protein, Torsin1b, is hypothesized to underlie the selective vulnerability of the brain where Torsin1b levels are low (Jungwirth et al, 2010; Kim et al, 2010; Tanabe et al, 2016). Consistent with this model, knockdown of Torsin1b significantly increased Torsin1a mislocalization in both cell lines (Figure 1C).…”

The DYT6 Dystonia Protein THAP1 Regulates Myelination within the Oligodendrocyte Lineage

“…Neurodevelopmental vulnerable periods are also observed in mouse models of DYT1 dystonia (Liang et al, 2014; Pappas et al, 2015; Tanabe et al, 2016; Weisheit and Dauer, 2015), indicating a potential pathophysiological theme for childhood-onset dystonias. In contrast to the myelination defects, motor abnormalities persist in N-CKO mice.…”