Evaluation of live-cell substrates for non-inhibitory small molecule chaperone therapy for Gaucher disease

Authors

• S Patnaik
• W Westbroek
• J Marugan
• E Sidransky

Abstract

Mutations in genes coding for lysosome-resident enzymes involved in distinct substrate turnover result in lysosomal storage disorders (LSDs), which are rare inborn metabolic disorders where lysosomal function is compromised. Gaucher disease (GD) results from mutations in GBA1, the gene that encodes for the enzyme glucocerebrosidase (GCase). Current treatments for GD do not cross the blood-brain barrier. Therefore, it is imperative to develop new therapies like small molecular chaperones that are effective in treating the entire GD spectrum. In recent years, GD type I has been shown to be associated with Parkinson disease (PD) and related synucleinopathies. Thus, discoveries made regarding the pathophysiology of GD and its treatment may lead to new therapies for other neurodegenerative disorders such as PD. One of the current approaches for developing alternative therapies for GD is the identification of small, non-inhibitory chaperones through high throughput screening (HTS) assays. It had been previously shown that the mutant enzyme still retains its catalytic activity and thus non-inhibitory chaperones can allow the lysosomal localization of the mutant enzyme. However, there is currently no efficient and/or precise method to evaluate non-inhibitory chaperones for GD or other LSDs. One of the difficulties in accurately identifying potential activating chaperones is the fact that non-inhibitory chaperones bind to sites other than the active site. To overcome this obstacle, we are developing substrates that can effectively identify the potency of non-inhibitory chaperones in the lysosomes of live cells.

Scientific Focus Area: Molecular Biology and Biochemistry

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