Histone deacetylase inhibitors prevent the degradation and restore the activity of glucocerebrosidase in Gaucher disease

• DOI: 10.1073/pnas.1119181109
• Publication Date: 2011-12-13T05:15:49Z
• Authors: Jie Lu; Chunzhang Yang; Masako Chen; Donald Y. Ye; Russell R. Lonser; Roscoe O. Brady; Zhengping Zhuang
• Keywords: Lactacystin; Protein Degradation; Proteostasis

Gaucher disease (GD) is caused by a spectrum of genetic mutations within the gene encoding lysosomal enzyme glucocerebrosidase (GCase). These often lead to misfolded proteins that are recognized unfolded protein response system and degraded through ubiquitin–proteasome pathway. Modulating this pathway with histone deacetylase inhibitors (HDACis) has been shown improve stability in other settings. To identify mechanisms involved regulation GCase determine effects HDACis on stability, we investigated most prevalent for nonneuronopathic (N370S) neuronopathic (L444P) GD cultured fibroblasts derived from patients HeLa cells transfected these mutations. The half-lives mutant correspond decreases levels enzymatic activity. was found bind Hsp70, which directed TCP1 proper folding, Hsp90, Using known HDACi (SAHA) unique small-molecule (LB-205), increased rescuing activity cells. increase quantity can be attributed increases half-life primarily decrease degradation rather than an chaperoned folding. reduce binding Hsp90 prevent subsequent ubiquitination proteasomal without affecting Hsp70 or TCP1. findings provide insight into pathogenesis indicate potent therapeutic potential HDAC treatment human misfolding disorders.