Abstract
Despite a century of intensive investigation the effective treatment of protein aggregation diseases remains elusive. Ordinarily, molecular chaperones ensure that proteins maintain their functional conformation. The appearance of misfolded proteins that aggregate implies the collapse of the cellular chaperone quality control network. That said, the cellular chaperone network is extensive and functional information regarding the detailed action of specific chaperones is not yet available. J proteins (DnaJ/Hsp40) are a family of chaperone cofactors that harness Hsc70 (heat shock cognate protein of 70 kDa) for diverse conformational cellular tasks and, as such, represent novel clinically relevant targets for diseases resulting from the disruption of proteostasis. Here we review incisive reports identifying mutations in individual J protein chaperones and the proteostasis collapse that ensues.
Highlights
Despite a century of intensive investigation the effective treatment of protein aggregation diseases remains elusive
The balance between protecting protein functional integrity and preventing accumulation of misfolded proteins is accomplished by a network of chaperone families including: J proteins (DnaJ/Hsp40), HspA (Hsp70), HspB HspC (Hsp90), HspD/E (Hsp60/Hsp10), HspH (Hsp110), CCT (TRiC) and numerous regulatory factors (Figure 1)
Named Hsp40 or DnaJ after the founding members of the family (Georgopoulos et al, 1980; Ohtsuka et al, 1990), we know that there are 49 J proteins in humans that range in molecular weight from 18–520 kDa and that while some J proteins are induced by heat most members of the J protein family are constitutively expressed (Zhao et al, 2008; Kakkar et al, 2012)
Summary
The appearance of misfolded proteins that aggregate implies the collapse of the cellular chaperone quality control network. J proteins (DnaJ/Hsp40) are a family of chaperone cofactors that harness Hsc (heat shock cognate protein of 70 kDa) for diverse conformational cellular tasks and, as such, represent novel clinically relevant targets for diseases resulting from the disruption of proteostasis. The quality control machinery constantly protects against the misfolding and aggregation of proteins that is inherent to continuous protein synthesis, generation of folding intermediates and molecular crowding of neural proteins. While it is widely accepted that J proteins maintain and restore protein balance several questions remain regarding the nature of changes to the chaperone network in age related neurodegenerative diseases (Soti and Csermely, 2002; Muchowski and Wacker, 2005; Kim et al, 2013; Labbadia and Morimoto, 2014).
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