Involvement of the ubiquitin-proteasome pathway and molecular chaperones in oculopharyngeal muscular dystrophy

Abstract

Oculopharyngeal muscular dystrophy (OPMD) is a late-onset autosomal dominant muscular dystrophy that results from small expansions of a polyalanine tract in the PABPN1 gene. Intranuclear inclusions are the pathological hallmark of OPMD. The mechanism by which protein aggregation in OPMD might relate to a toxic gain-of-function has so far remained elusive. Whether protein aggregates themselves are pathogenic or are the consequence of an unidentified underlying molecular mechanism is still unclear. Here, we report that protein aggregation in a cell model of OPMD directly impaires the function of the ubiquitin-proteasome pathway (UPP) as well as molecular chaperone functions. The proteasome inhibitor lactacystin causes significant increase of protein aggregation and toxicity. Moreover, overexpression of molecular chaperones (HSP40 and HSP70) suppressed protein aggregation and toxicity. We also provide evidence that mPABPN1-ala17 protein aggregation proportionally correlates with toxicity. Furthermore, we show that co-expression of chaperones in our OPMD cell model increases the solubility of mPABPN1-ala17 and transfected cell survival rate. Our studies suggest that molecular regulators of polyalanine protein solubility and degradation may provide insights into new mechanisms in OPMD pathogenesis. Further analysis of the cellular and molecular mechanisms by which UPP and molecular chaperones influence the degradation of misfolded proteins could provide novel concepts and targets for the treatment and understanding of the pathogenesis of OPMD and neurodegenerative diseases.

The formation of peripheral myelin protein 22 aggregates is hindered by the enhancement of autophagy and expression of cytoplasmic chaperones

“…Preventing the formation and/or aiding the refolding of small aggregates before the assembly of a large inclusion can explain this result. In culture models of Hsp40 and/or Hsp70 overexpression, the intracellular aggregation of several unrelated proteins was also suppressed (Cummings et al, 1998;Stenoien et al, 1999;Dul et al, 2001;Abu-Baker et al, 2003). In our model, GA-treatment, as compared to HS was more effective in preventing Lcinduced aggresome formation, likely because of the sustained expression of HSPs over time.…”

Modeling Oculopharyngeal Muscular Dystrophy in Myotube Cultures Reveals Reduced Accumulation of Soluble Mutant PABPN1 Protein

“…This suggests that aggregation of WT and expPABN1 is differentially regulated by the proteasome. Because proteasome inhibition affects expPABPN1 aggregation in non-muscle cells, 38 proteasome regulation of expPABPN1 accumulation may not be muscle specific. For each KEGG pathway P value, the number of deregulated genes and the corresponding percentage from the total annotated genes are indicated.…”

Inhibition of Proteasome Activity Promotes the Correct Localization of Disease-Causing α-Sarcoglycan Mutants in HEK-293 Cells Constitutively Expressing β-, γ-, and δ-Sarcoglycan

“…45 Activation of protein degradation through proteasome also occurs in the pathogenesis of other muscular dystrophies. 46,47 Evidence of proteasome involvement was recently obtained in the mdx mice, an animal model of Duchenne Muscular Dystrophy resulting from a spontaneous point mutation of dystrophin gene introducing a premature stop codon. The treatment with proteasome inhibitors was not only able to prevent degradation of the short dystrophin polypeptide, but also permitted its targeting to the cell membrane.…”