Loss of function of VCP/TER94 causes neurodegeneration in the Drosophila central nervous system.

Abstract

Mutations in several genes are linked to human frontotemporal lobar degeneration (FTLD) associated with TDP43- and/or ubiquitin-positive inclusions. However, it is not yet clear whether the underlying mechanism is a gain-of-function or a loss-of-function. To answer this question, we used Drosophila expressing RNAi against the FTLD-associated gene, TER94 (an ortholog of VCP/p97) and found that the knockdown (KD) of this gene caused premature lethality, a reduction in brain volume and alterations in the morphology of mushroom bodies. The changes caused by TER94 KD were rescued by wild-type TER94 but not by the human disease-linked A229E mutant, indicating that this mutant causes a loss-of-function. Alterations were also observed in pupal brains and were partially rescued by coexpression of MCM2, which is involved in control of the cell cycle. This is suggesting that dysregulation of neuronal proliferation caused the phenotypes. We also found that TER94 KD caused the disappearance of TBPH (an ortholog of TDP43/TARDBP) from nuclei. These data from Drosophila genetics suggest that VCP-linked FTLD is caused by a loss-of-function of VCP.