Protein Homeostasis in Amyotrophic Lateral Sclerosis: Therapeutic Opportunities?

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.

Rhodopsin: A Potential Biomarker for Neurodegenerative Diseases

“…Several studies have found a positive correlation between retinal thinning and ALS patients (Hubers et al, 2016;Mukherjee et al, 2017;Rojas et al, 2019). However, loose connections may be made regarding ALS and rhodopsin, as one study has found a correlation between ER stress and ALS pathogenesis (Webster et al, 2017). Subsequently, ER stress in photoreceptors also has a significant pathophysiological effect on the elimination of misfolded rhodopsin proteins (Chiang et al, 2015).…”

LRRK2-mediated phosphorylation of HDAC6 regulates HDAC6-cytoplasmic dynein interaction and aggresome formation

“…Protein homeostasis is maintained by the proteostasis network, a complex regulatory network that controls protein biosynthesis, folding, trafficking, and clearance. Failure of the proteostasis network to deal with misfolded and potentially toxic proteins ultimately is deleterious to cells; this appears to be especially the case for neurons, as exemplified by the common occurrence of aberrant protein folding and aggregate deposition in neurons in neurodegenerative disease 21 .…”

Laser-captured spinal cord motorneurons from ALS subjects show increased gene expression in vacuolar ATPase networks

“…Autophagy is also abnormal in both sALS and fALS [46]. Additional autophagy-related genes overexpressed in LCM-MN's from ALS subjects include DCTN1 (ALS/CTL=2.93) that encodes the p150 subunit of the transporter protein dynactin, and Rab7a (ALS/CTL= 3.98) that encodes the small GTPase Rab7 that regulates the maturation of autophagosomes, amphisomes, and late endosomes in cells [47].…”