Progressive Disruption of Cellular Protein Folding in Models of Polyglutamine Diseases

Abstract

Numerous human diseases are associated with the chronic expression of misfolded and aggregation-prone proteins. The expansion of polyglutamine residues in unrelated proteins is associated with the early onset of neurodegenerative disease. To understand how the presence of misfolded proteins leads to cellular dysfunction, we employed Caenorhabditis elegans polyglutamine aggregation models. Here, we find that polyglutamine expansions disrupted the global balance of protein folding quality control, resulting in the loss of function of diverse metastable proteins with destabilizing temperature-sensitive mutations. In turn, these proteins, although innocuous under normal physiological conditions, enhanced the aggregation of polyglutamine proteins. Thus, weak folding mutations throughout the genome can function as modifiers of polyglutamine phenotypes and toxicity.

Firefly luciferase mutants as sensors of proteome stress

“…Deficiency in cellular proteostasis capacity has been implicated in numerous human neurodegenerative diseases such as HD, PD and ALS which are caused by protein misfolding and aggregation. Many of these diseases affect preferentially the elderly, which is consistent with a gradual decline in the efficiency of protein quality control mechanisms during aging (Gidalevitz et al, 2006;Morimoto and Cuervo, 2009). …”

“…Indeed, several studies have shown that sequestration of metastable and essential cellular factors such as proteins involved in chromatin remodeling, transcription, translation, nuclear import and cytoskeletal structure by the aggregates is the major cause of observed toxicity in vivo (Bucciantini et al, 2002;Chai et al, 2002;Olzscha et al, 2011;Suhr et al, 2001). Aggregates can also interfere with the cellular defense mechanisms by altering protein folding homeostasis (Gidalevitz et al, 2006;Satyal et al, 2000), by blocking proteasome mediated degradation (Bence et al, 2001;Bennett et al, 2005) or by inhibiting autophagy . Other models suggest that the aggregates can engage in aberrant interaction with cellular membranes leading to the formation of membrane pores (Lashuel et al, 2002) or they can disturb cellular ion homeostasis (Quist et al, 2005), may cause mitochondrial dysfunction and oxidative stress (Muller et al, 2010) (Figure 8).…”

“…A considerable body of experimental evidence suggests that formation of Htt inclusions is a protective mechanism, employed by cells to sequester potentially dangerous soluble oligomers of misfolded Htt (Arrasate et al, 2004;Bodner et al, 2006;Miller et al, 2010;Takahashi et al, 2008). This sequestration may reduce the number of exposed regions in mutant Htt that otherwise would titrate away cellular folding factors, putting the folding of the metastable proteome in jeopardy (Gidalevitz et al, 2006;Satyal et al, 2000).…”

“…During aging, there is a progressive decline in the efficiency of protein quality control mechanisms (Gidalevitz et al, 2006;Morimoto, 2008) (Figure 12). This deficit in the proteostasis capacity predisposes individuals to many late-age onset diseases including neurodegenerative diseases such as AD, PD and HD and other maladies like diabetes type II, myopathies etc.…”

“…residues results in the formation of aggregates in the nucleus DiFiglia et al, 1997) and leads to cellular toxicity. Moreover, expression of polyQ-containing proteins in the nematode C. elegans has been shown to compromise the cellular folding capacity and to disrupt proteostasis (Gidalevitz et al, 2006).…”