Study of Wolfram Syndrome in neuronal cell models

[摘要] Wolfram Syndrome (WS) is a rare autosomal recessive disease characterised by insulin-dependent diabetes mellitus, optic nerve atrophy. The current study demonstrated that neuronal cells depleted of WFS1 protein, showed significantly elevated expression of the ER stress markers indicating an enhanced ER stress response. This was accompanied by increased apoptosis and impaired cell cycle progression. WFS1 depletion also resulted in decreased expression of Na+/K+ ATPase beta1 subunit and Vacuolar ATPase (V-ATPase) V1A subunit. The elevated expressions of ER stress markers, but not the decreased expression of pump subunits, were reversed by adenoviral over-expression of BiP/GRP78. Protein degradation assays showed more rapid degradation of both pump subunits in WFS1 depleted cells compared with controls. A novel interaction between WFS1 and the V1A subunit of the vacuolar-type H+-ATPase (proton pump) was demonstrated by co-immunoprecipitation in overexpression system and with endogenous proteins. The interaction was mapped to the WFS1-N terminal, but not the C-terminal domain. In conclusion, this study shows that WFS1 has a specific interaction with the V1A subunit of H+ V-ATPase.Chemical and molecular chaperones TUDCA, GRP78 and the histone deacetylase inhibitor VPA showed promising results in providing protection against ER stress induced apoptosis in WFS1 depleted neuronal cells.

[发布机构] University:University of Birmingham;Department:School of Clinical and Experimental Medicine

[关键词] R Medicine;R Medicine (General)