Overexpression of a conserved HSP40 chaperone reduces toxicity of several neurodegenerative disease proteins

Abstract

TDP-43 and FUS are DNA/RNA binding proteins associated with neuronal inclusions in amyotrophic lateral sclerosis (ALS) patients. Other neurodegenerative diseases are also characterized by neuronal protein aggregates, e.g. Huntington's disease, associated with polyglutamine (polyQ) expansions in the protein huntingtin. Here we discuss our recent paper establishing similarities between aggregates of TDP-43 that have short glutamine and asparagine (Q/N)-rich modules and are soluble in detergents, with those of polyQ and PIN4C that have large Q/N-rich domains and are detergent-insoluble. We also present new, similar data for FUS. Together, we show that like overexpression of polyQ or PIN4C, overexpression of FUS or TDP-43 causes inhibition of the ubiquitin proteasome system (UPS) and toxicity, both of which are mitigated by overexpression of the Hsp40 chaperone Sis1. Also, in all cases toxicity is enhanced by the [PIN] prion. In addition, we show that the Sis1 mammalian homolog DNAJBI reduces toxicity arising from overexpressed FUS and TDP-43 respectively in human embryonic kidney cells and primary rodent neurons. The common properties of these proteins suggest that heterologous aggregates may enhance the toxicity of a variety of disease-related aggregating proteins, and further that chaperones and the UPS may be key therapeutic targets for diseases characterized by protein inclusions.

Calcium-responsive transactivator (CREST) toxicity is rescued by loss of PBP1/ATXN2 function in a novel yeast proteinopathy model and in transgenic flies

“…While TDP-43 and FUS quickly form cytoplasmic aggregates in yeast with little or no nuclear localization [31,32,37,57,[75][76][77], we found here that CREST appeared in nuclear aggregates with only occasional cytoplasmic foci. While the ALS associated proteins TDP-43, FUS and SOD1 form aggregates in patients, model systems and in vitro, these aggregates are sometime but not always classical amyloids.…”

“…Some data support the hypothesis that the [PIN + ] aggregates of RNQ1 cross-seed aggregation of heterologous proteins such as SUP35 and polyQ. Likewise some, but not all evidence suggests that the [PIN + ] aggregates bind proteins such as chaperones that would otherwise inhibit aggregation of the heterologous SUP35 or polyQ protein, thereby enhancing their aggregation [18][19][20][21][22][23][24][25]27] We recently showed that toxicity of TDP-43 and FUS is enhanced by the presence of [PIN + ] [37,57]. Both of these proteins contain Q/N-rich regions and co-aggregate with polyQ disease protein alleles of huntingtin [64,65].…”

“…Since the presence of the [PIN + ] prion causes enhanced toxicity of the human genes huntingtin/polyQ, TDP-43 and FUS [28,36,37,57] , we asked if [PIN + ] would likewise increase toxicity of CREST and found that it did ( Fig. 2a).…”

Human DnaJB6 Antiamyloid Chaperone Protects Yeast from Polyglutamine Toxicity Separately from Spatial Segregation of Aggregates

“…Several earlier studies show that, aside from simply preventing spreading of aggregates, similar assembly and spatial segregation of aggregates of polyQ and other misfolded proteins by other PQC factors is crucial for protection from toxicity (9,12,17,19,20,23,24,44). These and other studies support a view that such sequestration of toxic aggregates is a general response by the cell to defend against toxicity of misfolded proteins.…”

“…Human DnaJB6, an Hsp70 cochaperone, protects yeast and mammalian systems from Huntington's disease-related polyglutamine (polyQ) toxicity that is caused by expressing a disease-related version of Huntingtin exon 1 containing 103 to 119 glutamines and green fluorescent protein (here HttQ103-GFP) (7,8). DnaJB6 is the J-protein most closely related to the yeast Sis1, which also protects cells from toxicity due to protein misfolding (9)(10)(11)(12).…”