Reply: Hereditary spastic paraplegia caused by a mutation in the VCP gene VCP: A Jack of all trades in neuro- and myodegeneration?

Abstract

Sir, de Bot et al. report on a novel autosomal-dominant form of hereditary spastic paraplegia due to a valosin-containing protein (VCP) missense mutation. Mutations of the human VCP gene on chromosome 9p13.3 have previously been described to cause IBMPFD (inclusion body myopathy with early onset Paget’s disease of bone and frontotemporal dementia, OMIM #167320) (for current review on IBMPFD see Nalbandian et al. , 2011) and ALS14 (amyotrophic lateral sclerosis with or without frontotemporal dementia, OMIM #613954) (for current review on ALS see de Carvalho and Swash, 2011). In the light of the complexity of VCP’s multiple cellular functions, dissecting the molecular pathogenesis of these three diseases is a true scientific challenge. VCP is a ubiquitously expressed, abundant and evolutionarily highly conserved member of the type II AAA-ATPase family (ATPases associated with a wide variety of cellular activities). The targeted ablation of VCP in mouse as well as of its orthologue in fruit fly, yeast and a protist is a lethal event (Frohlich et al. , 1991; Leon and McKearin, 1999; Lamb et al. , 2001; Muller et al. , 2007). VCP plays essential roles in a wide variety of cellular processes comprising nuclear envelope reconstruction, cell cycle, post-mitotic Golgi reassembly, suppression of apoptosis, DNA damage response and endocytosis. In addition, VCP has been attributed to exert central roles in several protein quality control pathways (for review of the multiple functions of VCP refer to Yamanaka et al. , 2012). The pathological consequences of VCP missense mutations have thus far primarily been studied in the context of IBMPFD. Within the large group of human protein aggregation diseases, IBMPFD has a unique role, because VCP- and ubiquitin-positive pathological protein aggregates are present in both neuronal and striated muscle cells (Schroder et al. , 2005; Hubbers …