The role of molecular chaperones in human misfolding diseases

Abstract

a b s t r a c tHuman misfolding diseases arise when proteins adopt non-native conformations that endow them with a tendency to aggregate and form intra-and/or extra-cellular deposits. Molecular chaperones, such as Hsp70 and TCP-1 Ring Complex (TRiC)/chaperonin containing TCP-1 (CCT), have been implicated as potent modulators of misfolding disease. These chaperones suppress toxicity of disease proteins and modify early events in the aggregation process in a cooperative and sequential manner reminiscent of their functions in de novo protein folding. Further understanding of the role of Hsp70, TRiC, and other chaperones in misfolding disease is likely to provide important insight into basic pathomechanistic principles that could potentially be exploited for therapeutic purposes.

Proteostasis impairment in protein-misfolding and -aggregation diseases

“…Multiple lines of evidence suggest that polyQ expanded proteins titrate chaperones away from their clients, leading to proteostasis impairment [44,74,100,109,110]. Conversely, overexpression of various chaperones, such as members of the Hsp70 system, suppresses polyQ toxicity [3, 69,75].…”

“…The importance of proteostasis impairment in the pathogenesis of aggregate deposition disorders is reinforced by the existence of familial forms of neurodegeneration which are caused by mutation of PN components [75]. For example, loss-of-function mutations in the ubiquitin ligase PARKIN and the PARKIN-related kinase PINK1 are the cause of early-onset PD [76,77].…”

Reactivation of protein aggregates by mortalin and Tid1—the human mitochondrial Hsp70 chaperone system

“…Molecular chaperones serve as a first line of defense against uncontrolled unfolding and aggregation of proteins (Broadley and Hartl 2009). Mitochondria serve as the major site of ATP production, a process which involves electron transfer and free radical production.…”

Firefly luciferase mutants as sensors of proteome stress

“…Hsp70 members are highly multifunctional proteins that have been shown to play a key role in proteome maintenance, such as in de novo protein folding (co-or post-translational), protein translocation across membranes (Lyman and Schekman, 1997;Matlack et al, 1999;Young et al, 2003), refolding of stress damaged proteins (Ben-Zvi et al, 2004;Schroder et al, 1993;Sharma et al, 2010), in preventing protein aggregation (Auluck et al, 2002;Broadley and Hartl, 2009;Klucken et al, 2004;Sakahira et al, 2002;Warrick et al, 1999), disaggregation (Ben-Zvi and Goloubinoff, 2001;Diamant et al, 2000;Liberek et al, 2008;Shorter, 2011) and degradation of irreparable misfolded proteins (Bercovich et al, 1997;Fisher et al, 1997;Urushitani et al, 2004). These essential and diverse cellular functions of Hsp70 are attributed to its physical interaction with various co-chaperones such as Hsp40, NEFs and with proteins such as HIP, HOP and CHIP.…”