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

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.DOI: http://dx.doi.org/10.7554/eLife.17834.001

Ubiquitin- and ATP-dependent unfoldase activity of P97/VCP•NPLOC4•UFD1L1 is enhanced by a mutation that causes multisystem proteinopathy

“…On the other hand, IBMPFD mutant proteins hydrolyze ATP at a faster rate (20, 63–65). Whereas it has been speculated that the increase in ATP hydrolysis might be due to an uncoupling of substrate binding via the N domain to mechanochemical transduction in the D2 domain (54, 68), studies in Drosophila point to an increase in function for the mutant p97 (61, 67, 69).…”

“…Is this truly due to enhanced activity, or do the mutations actually cause reduction-of-function through a dominant-negative mechanism, with mutant protomers poisoning mixed hexamers? Studies in Drosophila support the idea that the pathogenesis of IBMPFD mutations stems from elevated p97 activity, resulting in increased processing of TDP-43 (69) and mitofusin (61). As of yet there remains no biochemical assay that measures p97’s presumed core function of protein unfolding that would enable a direct test of this hypothesis in a defined system.…”

“…However, the mechanism of pathogenesis is not understood in either case. It has been suggested at various times that pathogenesis arises from a failure of autophagy, endosomal sorting, clearance of leaky lysosomes, mitochondrial homeostasis, or mTOR regulation (56, 57, 8, 58– 61). Regardless of the cellular target, the molecular-level defect remains obscure.…”

Review: Modelling the pathology and behaviour of frontotemporal dementia

“…Mitochondrial defects are also observed in VCP mutant mice [117,118,120], though this has not been investigated in the models exhibiting FTD-like phenotypes. However, this has been recapitulated in Drosophila where VCP mutants promote mitofusin degradation leading to disrupted fission of mitochondria [125]. Overall, these models suggest VCP mutations not only disrupt the ubiquitin protease system, but also autophagy and mitophagy pathways.…”

Drosophila VCP/p97 Mediates Dynein-Dependent Retrograde Mitochondrial Motility in Axons

“…The Drosophila genome shows a high degree of similarity to the human genome, and many fundamental regulatory processes of the nervous systems are conserved between humans and flies (Wang and Schwarz, 2009a). As a result, Drosophila has been successfully used to establish diverse human neurodegenerative disease models (Gunawardena et al, 2003;Clark et al, 2006;Park et al, 2006;Wang et al, 2007;Kim et al, 2013;Zhang et al, 2017). In Drosophila larvae, the cell bodies of central nervous system neurons are located in the ventral nerve cord.…”