Amyotrophic lateral sclerosis (ALS)It is not surprising that one of the common progressive motor neuron diseases, ALS, is also genetically connected to mutations in degradation mechanisms with various etiologies. Most ALS is also sporadic, two of the familial forms of ALS are mainly associated with simple monogenic factors, the SOD mutation (D90A) and a large hexanucleotide repeat expansion (GGGGCC) 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 vesicular trafficking proteins in autophagy have suggested a fragile proteostasis capacity in subjects vulnerable neurons (Bedford et al., 2008; Deng et al., 2011; Paine et al., 2013; Johnson et al., 2010). Recent genetic and biochemical studies have revealed that mutations in a unique PXX repeat region of UBQLN2 which is one of the family of ubiquitin-like proteins are causative in ALS. The different UBQLN2 mutations are present in the typical skein inclusion that is a hallmark of ALS pathology. In the detailed functional relevance of the ubiquitin-like domain (UBL) and ubiquitin-binding domain (UBA) of UBQLN2 still need further clarification, the degradation of the UPS reporter is slowed in neuroblastoma cells transfected with UBQLN2 mutations (Deng et al., 2011). The interaction of another ubiquilin family member (UBQLN1) with TAR polyubiquitinated DNA-binding protein 43 (TDP43), also genetically linked to ALS, may implicate critical functions of the ubiquilin family in ALS pathology ( Kim et al., 2009). Further evidence The link between ALS and the UPS component comes from the identification of mutations in valosin content...... half of the article ...... Alternatively, loss of VAPB functions in VAPB mutations linked to ALS was suggested by a recent genetic study using zebrafish and mouse models. Thus, deletion of VAPB in zebrafish caused swimming deficits, and deletion of VAPB in mice led to mild motor deficits (Kabashi et al., 2013). Presumably, the increasing number of different positional mutations in VAPB linked to sporadic ALS might indicate a susceptibility to increased neuronal weakness in the loss 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 for the onset of protein aggregation diseases. Reduced activity or inefficient assembly of the proteasome in the aging process further exacerbates the collapse of proteostasis.