Abstract
Protein homeostasis (proteostasis), the correct balance between production and degradation of proteins, is essential for the health and survival of cells. Proteostasis requires an intricate network of protein quality control pathways (the proteostasis network) that work to prevent protein aggregation and maintain proteome health throughout the lifespan of the cell. Collapse of proteostasis has been implicated in the etiology of a number of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), the most common adult onset motor neuron disorder. Here, we review the evidence linking dysfunctional proteostasis to the etiology of ALS and discuss how ALS-associated insults affect the proteostasis network. Finally, we discuss the potential therapeutic benefit of proteostasis network modulation in ALS.
Highlights
The proteostasis network is a complex regulatory network that maintains proteostasis
The presence of chaperones, such as heat shock cognate protein of 70 kDa (Hsc70) and heat shock protein of 90 kDa (Hsp90) in detergent-insoluble neuronal aggregates in the SOD1G93A transgenic mouse model of familial amyotrophic lateral sclerosis (ALS) and post-mortem human sporadic ALS cases indicates that altered chaperone function may contribute to disease pathogenesis (Watanabe et al, 2001; Basso et al, 2009; Bergemalm et al, 2010)
We found that C9orf72 is an effector of Rab1a that facilitates trafficking of the ULK1 initiation complex to the phagophore during autophagy initiation (Webster et al, 2016a) while others demonstrated that a complex of C9orf72, SMCR8, and WDR41 acts as a guanine nucleotide exchange factor for RAB8a and RAB39b further down the autophagy pathway during autophagosome maturation (Sellier et al, 2016)
Summary
The proteostasis network is a complex regulatory network that maintains proteostasis. The proteostasis network consists of several pathways that control protein biosynthesis, folding, trafficking, and clearance (degradation) and responds to specific protein stress pathways such as the unfolded protein response (UPR) in the endoplasmic reticulum (ER), the mitochondrial UPR and the cytosolic heat shock response (Figure 1). Specific protein stress pathways such as the heat shock response and UPR are activated to boost chaperone levels and aid refolding or to stimulate removal of terminally misfolded proteins to prevent protein aggregation and proteotoxic stress. Degradation by the proteasome requires protein unfolding and relies on chaperones to prevent proteins from aggregating (reviewed in Hershko and Ciechanover, 1998). As the ability of cells to maintain proteostasis declines with aging it is not surprising that aberrant protein folding and aggregate deposition in neurons is a common feature of age-associated neurodegenerative disease. We review the evidence linking dysfunctional proteostasis to the etiology of amyotrophic lateral sclerosis (ALS) and discuss how ALS-associated insults affect the proteostasis network
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