Relative tissue expression of homologous torsins can explain the neuronal specific importance of DYT1 dystonia‐associated torsinA

Abstract

A three base-pair deletion in the widely expressed TOR1A gene causes the childhood onset, neurological disease of DYT1 dystonia. Mouse Tor1a gene knockout also specifically affects the developing nervous system. However, in both cases, the basis of neuronal tissue specificity is unknown. TorsinA is one of four predicted mammalian torsin ATPases associated with assorted cellular activities (AAA1) proteins, raising the possibility that expression of a functionally homologous torsin compensates for torsinA loss in non-neuronal tissues. We find that all four mammalian torsins are endoplasmic reticulum resident glycoproteins. TorsinA, torsinB and torsin2 are all present in large M r complexes, which suggests that each assembles into an oligomeric AAA1 enzyme. Introducing a mutation (WB EQ ) that typically stabilizes AAA1 proteins in a substratebound state causes torsinA and torsinB to associate with a shared nuclear envelope (NE) binding partner and this NE localization requires the torsinA interacting protein, lamina associated polypeptide 1. Although torsin proteins are widely expressed in the adult mouse, we identified that embryonic neuronal tissues contain relatively low torsinB levels. Therefore, our results reveal that torsinB expression inversely correlates with the cell and developmental requirement for torsinA. In conclusion, multiple cell types appear to utilize torsin AAA1 proteins and differential expression of torsinB may contribute to both the neuronal specific importance of torsinA and the symptom specificity of DYT1 dystonia.

DYT-TOR1A dystonia: an update on pathogenesis and treatment

“…"Blebs" are thought to be intermediate products of abnormal NPC biogenesis that are stalled before INM and ONM fusion (Dorboz et al, 2014;Demircioglu et al, 2019;Fichtman et al, 2019). Although no mature NPCs are found within "blebs, " specific nucleoporins associated with multiple subcomplexes that construct NPCs have been found within these "blebs" (Jungwirth et al, 2010;Dorboz et al, 2014;Kayman-Kurekci et al, 2014;Fichtman et al, 2019). In addition, the diagnostically relevant components of these vesicles, such as the protein myeloid leukemia factor 2 (MLF2) and K48-linked ubiquitin (Ub) chains, are not well-characterized.…”