Loss of Function of VCP/TER94 Causes Neurodegeneration

Overview

Journal Dis Model Mech

Specialty General Medicine

Date 2024 Dec 4

PMID 39629589

Authors

Kohei Tsumaki

Christian J F Bertens

Minoru Nakayama

Saya Kato

Yuki Jonao

Ayu Kuribayashi

Konosuke Sato

Shota Ishiyama

Momoko Asakawa

Riko Aihara

Yuki Yoshioka

Hidenori Homma

Hikari Tanaka

Kyota Fujita

Hitoshi Okazawa

Masaki Sone

Affiliations

Soon will be listed here.

Abstract

Variants 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 one. To answer this question, we used Drosophila expressing double-stranded RNA against the FTLD-associated gene TER94 (an ortholog of VCP/p97) and found that the knockdown (KD) of this gene caused premature lethality, 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 loss of function. Alterations were also observed in pupal brains and were partially rescued by co-expression of Mcm2, which is involved in control of the cell cycle, suggesting that dysregulation of neuronal proliferation caused the phenotypes. TER94 KD also 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 loss-of-function of VCP.

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