Amyotrophic lateral sclerosis (ALS)
It is not surprised that one of the common progressive motor neuronal disease, ALS, is also genetically connected to the mutations of degradation machineries with varied etiology. Even the majority of ALS is sporadic, two of familial ALS is mainly associated with simple monogenic factors, the mutation of SOD (D90A) and a large hexanucleotide (GGGGCC) repeat expansion in chromosome 9 open reading frame 72 (C9ORF72). However, growing evidence of genetic mutations in proteostasis factors discovered in familial ALS such as, UBQLN2, VCP/CDC48 in the UPS and SQSTM1/p62, VAPB and some of the vesicular traffic proteins in autophagy have been suggesting a fragile capacity of proteostasis in vulnerable neurons (Bedford et al., 2008; Deng et al., 2011; Paine et al., 2013; Johnson et al., 2010).
Recent genetic and biochemical study revealed that mutations in a unique PXX repeat region of UBQLN2 which is one of ubiquitin like protein family are causative in ALS. The different mutations of UBQLN2 are present in the typical skein-like inclusion which is a hallmark of ALS pathology. In detailed functional relevance of ubiquitin like domain (UBL) and ubiquitin association domain (UBA) of UBQLN2 still need further elucidation, degradation of UPS reporter slowed in neuroblastoma cells transfected with mutations of UBQLN2 (Deng et al., 2011). Interaction of another member of the ubiquilin family (UBQLN1) with polyubiquitylated TAR DNA-binding protein 43 (TDP43) which is also genetically linked to ALS may imply fundamental functions of ubiquilin family in ALS pathology (Kim et al., 2009).
Another evidence of linkage between ALS and the UPS component came from the identification of mutations in valosin containing protein (VCP/p97/Cdc48) in familial ALS and inclusion body myopathy, Paget disease of bone, and frontotemporal dementia (IBMPFD) (Johnson et al., 2010; Tresse et al., 2010). In fact, VCP is the hexameric AAA-ATPase super family. It has been involved in various cellular pathways as a key regulator of proteolysis with its functional adaptor proteins. Thus, interaction of UBX domain or interaction motifs in different adaptor proteins with a globular N-terminal domain of VCP modulates activity of VCP and functional diversities. Intrinsic nature of VCP as ATPase activity and ability of recruiting distinct adaptor proteins under the cellular context brings it to a central location of proteolysis. For example, it could extract ubiquitin conjugated client proteins from ER by ATP hydrolysis with assistance of adaptor proteins, NPL4 and UFD1and essentially escorts them to proteasomal degradation. In similar way, VCP/ NPL4/UFD1 complex mediated degradation of damaged mitochondria with cooperation of E3 ligase, PAKIN (Kim et al., 2013; Meyer et al., 2012; Stolz et al., 2011; Tanaka et al., 2010). Accumulated evidence have suggested that VCP also determines the regulation of DNA damage repair, cell cycle controlling and...