Amyotrophic Lateral Sclerosis

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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 contai... ... middle of paper ... ...ernatively, loss of VAPB functions in VAPB mutations linked to ALS has been suggested by a resent genetic study using zebra fish and mice models. Thus, knockdown of VAPB in zebra fish was causative to swimming deficits and knockout of VAPB in mice led mild motor deficits (Kabashi et al., 2013). Presumably, arising number of different positional mutations at VAPB linked to sporadic ALS might indicate susceptibility of neuronal weakness increased in losing of its native function (Ingre et al., 2013). Aging / HSF1 / UPR (Ben-Zvi et al., 2009; Cohen et al., 2012; Denny et al., 2013) Although numerous stress conditions lead to an imbalance of proteostasis, aging is the most deleterious risk factor for the onset of protein aggregation diseases. The declined activity or inefficient assembly of the proteasome in aging process exacerbate collapsing of proteostasis further.

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