The intersection of lysosomal and endoplasmic reticulum calcium with autophagy defects in lysosomal diseases

Abstract

The lysosomal storage disorders (LSDs) encompass a group of more than 50 inherited diseases characterized by the accumulation of lysosomal substrates. Two-thirds of patients experience significant neurological symptoms, but the mechanisms of neurodegeneration are not well understood. Interestingly, a wide range of LSDs show defects in both autophagy and Ca²⁺ homeostasis, which is notable as Ca²⁺ is a key regulator of autophagy. The crosstalk between these pathways in the context of LSD pathogenesis is not well characterized, but further understanding of this relationship could open up promising therapeutic targets. This review discusses the role of endoplasmic reticulum and lysosomal Ca²⁺ in autophagy regulation and highlights what is known about defects in autophagy and Ca²⁺ homeostasis in two LSDs, Niemann-Pick type C disease and Gaucher disease.

Keywords: Autophagy; Calcium; Endoplasmic reticulum; Gaucher disease; Lysosome; Niemann-Pick type C disease.