Unraveling the role of cellular phosphatases in lysosome function and storage diseases

Abstract

Eukaryotic cellular pathways are maintained and coordinated through biomolecule turnover, which includes synthesis, trafficking, degradation of cellular components and their reutilization. The process of biomolecule degradation has been shown to modulate the cellular homeostasis. Lipid degradation in mammalian cells occurs in membrane-bound organelles called lysosomes and is carried out by acid hydrolases. Mutations in the lysosomal enzymes or their defective trafficking lead to the accumulation of degradative substrates resulting in lysosome dysfunction, observed in a group (~60 types) of genetic diseases known as lysosomal storage disorders/diseases (LSDs). In the past one decade, LSDs in India have surged and 374 cases have been reported so far, wherein 34% patients suffer from Gaucherand#8223;s disease. In line, Gaucherand#8223;s disease has been the most common LSD reported in the world. This disorder is caused by mutations in the gene GBA1 that encodes for lysosomal enzyme acid and#61538;-glucosidase or and#61538;-glucocerebrosidase (and#61538;-GC). Most commonly, mutations in and#61538;-GC lead to its misfolding and is subjected to ER-associated proteasomal degradation (ERAD) that impairs the trafficking of enzyme to lysosomes. This process results in accumulation of the substrate glucosylceramide causing lysosome dysfunction that lead to hepatomegaly and splenomegaly. It has been shown that few of the and#61538;-GC mutants lead to the neuropathic form of the disease, which affects the central nervous system. Currently, enzyme replacement (ERT) and substrate reduction (SRT) therapies are used to cure the non-neuropathic Gaucherand#8223;s disease. In this study, we aimed to modulate the cellular pathways that control the folding and trafficking of mutant and#61538;-GC to lysosome. Cellular phosphatases/kinases are known to alter these proteostasis pathways through a post-translation modification. Thus, we studied the role of phosphatases and kinases in regulating lysosome function following their effect on Gaucherand#8223;s disease. The current study entitled as Unraveling the role of c...