Valosin-containing protein (VCP/p97) inhibitors relieve Mitofusin-dependent mitochondrial defects due to VCP disease mutants.

Ming Guo,Bruce A Hay,Ting Zhang,David Chan,Prashant Mishra

doi:10.7554/elife.17834

Abstract

Missense mutations of valosin-containing protein (VCP) cause an autosomal dominant disease known as inclusion body myopathy, Paget disease with frontotemporal dementia (IBMPFD) and other neurodegenerative disorders. The pathological mechanism of IBMPFD is not clear and there is no treatment. We show that endogenous VCP negatively regulates Mitofusin, which is required for outer mitochondrial membrane fusion. Because 90% of IBMPFD patients have myopathy, we generated an in vivo IBMPFD model in adult Drosophila muscle, which recapitulates disease pathologies. We show that common VCP disease mutants act as hyperactive alleles with respect to regulation of Mitofusin. Importantly, VCP inhibitors suppress mitochondrial defects, muscle tissue damage and cell death associated with IBMPFD models in Drosophila. These inhibitors also suppress mitochondrial fusion and respiratory defects in IBMPFD patient fibroblasts. These results suggest that VCP disease mutants cause IBMPFD through a gain-of-function mechanism, and that VCP inhibitors have therapeutic value.

Highlights

IBMPFD is an autosomal dominant disease that afflicts multiple body systems (Kimonis et al, 2008a). 90% of IBMPFD patients display skeletal muscle weakness, the primary and earliest symptom of IBMPFD (Weihl et al, 2009)
Since valosin-containing protein (VCP) disease mutants have dramatic muscle phenotypes in humans and mouse models, and these are associated with defects in mitochondrial structure and function, we first examined the consequences of manipulating VCP levels
While expression of VCP under the control of the pan-muscle Gal4 drivers 24B-Gal4 or Mef2-Gal4 resulted in 100% adult lethality, expression of wildtype VCP under indirect flight muscle (IFM) control, which provides a pulse of expression in late pupal stages and early adulthood, gave rise to viable flies with intact and healthy muscle following adult eclosion

Summary

Introduction

IBMPFD is an autosomal dominant disease that afflicts multiple body systems (Kimonis et al, 2008a). 90% of IBMPFD patients display skeletal muscle weakness (myopathy), the primary and earliest symptom of IBMPFD (Weihl et al, 2009). IBMPFD is an autosomal dominant disease that afflicts multiple body systems (Kimonis et al, 2008a). One-third of the patients will develop frontotemporal dementia (Weihl et al, 2009; Kimonis et al, 2008b). Single missense mutations of p97/cdc48/Valosin-containing protein (VCP) cause fully penetrant IBMPFD (Watts et al, 2004). VCP encodes a highly conserved and abundant AAA+ ATPase which participates in multiple cellular processes (Meyer et al, 2012). VCP functions in multiple contexts that include protein quality control in the endoplasmic reticulum (Ye et al, 2001; Shih and Hsueh, 2016), chromatin

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