Levels of DNAJB family members (HSP40) correlate with disease onset in patients with spinocerebellar ataxia type 3

Abstract

In polyglutamine disorders, the length of the expanded CAG repeat shows a strong inverse correlation with the age at disease onset, yet up to 50% of the variation in age of onset is determined by other additional factors. Here, we investigated whether variations in the expression of heat shock proteins (HSP) are related to differences in the age of onset in patients with spinocerebellar ataxia (SCA)3. Hereto, we analysed the protein expression levels of HSPA1A (HSP70), HSPA8 (HSC70), DNAJB (HSP40) and HSPB1 (HSP27) in fibroblasts from patients and healthy controls. HSPB1 levels were significantly upregulated in fibroblasts from patients with SCA3, but without relation to age of onset. Exclusively for expression of DNAJB family members, a correlation was found with the age of onset independent of the length of the CAG repeat expansion. This indicates that DNAJB members might be contributors to the variation in age of onset and underlines the possible use of DNAJB proteins as therapeutic targets.

Firefly luciferase mutants as sensors of proteome stress

“…In HEK 293T cells, DnaJB1 is moderately expressed and is highly inducible upon heat stress (Hageman et al, 2010;Hageman et al, 2011). It has been shown that DnaJB1 suppresses the aggregation of polyQ proteins (Rujano et al, 2007;Zijlstra et al, 2010) and also prevents luciferase aggregation during heat stress (Hageman et al, 2010). Moreover, it has been demonstrated that overexpression of Hsp70 and DnaJB1 facilitates the degradation of polyQ expanded forms of the androgen receptor (Bailey et al, 2002).…”

Genetic risk factors for modulation of age at onset in Machado-Joseph disease/spinocerebellar ataxia type 3: a systematic review and meta-analysis

“…A large body of evidence has established that AO is not entirely explained by CAGexp, which explains 50% to 60% of the variability in AO,5–8 and that AO should be modulated by additional genetic and/or environmental factors. Several candidates have been proposed, such as apolipoprotein E genotypic status,9–11 CAG length at normal ATXN3 8 12 13 and ATXN2 6 8 alleles, and protein levels of the DNAJB1 chaperone 14…”

Background-dependent effects of polyglutamine variation in the Arabidopsis thaliana gene ELF3

“…For example, TR copy number mutations that expand polyglutamine (polyQ) tracts past a threshold number of glutamines can cause incurable neurodegenerative diseases, such as Huntington disease and Spinocerebellar Ataxias (2,3). PolyQ tract length correlates with onset and severity of polyQ expansion disorders, but for intermediate polyQ tracts this correlation is far weaker (4)(5)(6)(7)(8), suggesting that genetic and environmental modifiers exist (9)(10)(11)(12). Despite their potential for pathogenicity, variable polyQ tracts occur frequently in eukaryotic proteins, many of them functioning in development and transcription (1,(13)(14)(15).…”