Neurodegenerative Lysosomal Storage Disorders: TPC2 Comes to the Rescue!

Abstract

Lysosomal storage diseases (LSDs) resulting from inherited gene mutations constitute a family of disorders that disturb lysosomal degradative function leading to abnormal storage of macromolecular substrates. In most LSDs, central nervous system (CNS) involvement is common and leads to the progressive appearance of neurodegeneration and early death. A growing amount of evidence suggests that ion channels in the endolysosomal system play a crucial role in the pathology of neurodegenerative LSDs. One of the main basic mechanisms through which the endolysosomal ion channels regulate the function of the endolysosomal system is Ca2+ release, which is thought to be essential for intracellular compartment fusion, fission, trafficking and lysosomal exocytosis. The intracellular TRPML (transient receptor potential mucolipin) and TPC (two-pore channel) ion channel families constitute the main essential Ca2+-permeable channels expressed on endolysosomal membranes, and they are considered potential drug targets for the prevention and treatment of LSDs. Although TRPML1 activation has shown rescue effects on LSD phenotypes, its activity is pH dependent, and it is blocked by sphingomyelin accumulation, which is characteristic of some LSDs. In contrast, TPC2 activation is pH-independent and not blocked by sphingomyelin, potentially representing an advantage over TRPML1. Here, we discuss the rescue of cellular phenotypes associated with LSDs such as cholesterol and lactosylceramide (LacCer) accumulation or ultrastructural changes seen by electron microscopy, mediated by the small molecule agonist of TPC2, TPC2-A1-P, which promotes lysosomal exocytosis and autophagy. In summary, new data suggest that TPC2 is a promising target for the treatment of different types of LSDs such as MLIV, NPC1, and Batten disease, both in vitro and in vivo.

Deletion of Dictyostelium tpc2 gene forms multi‐tipped structures, regulates autophagy and cell‐type patterning

“…Lower acidic nature of acidic vesicles by tpc2 knockdown was also reported in melanocytes (Ambrosio et al, 2016b. ) Lysosomal exocytosis and autophagy was promoted by small molecule agonist of TPC2, TPC2-A1-P, which promotes lysosomal exocytosis and autophagy in lysosomal storage disease (Prat-Castro et al, 2022). Multi-tipped phenotype and delayed development in starving tpc2 − cells could be linked to autophagy inhibition; mutation in autophagic marker genes also shows similar phenotypes and can be correlated to autophagy inhibition (Calvo-Garrido et al, 2010).…”

Pathological Functions of Lysosomal Ion Channels in the Central Nervous System

“…Neurological symptoms or signs are prevalent in most LSDs, including developmental delays, seizures, acroparesthesia, motor weakness, premature mortality, and extrapyramidal manifestations [ 153 ]. Emerging evidence suggests that ion channels in the endolysosomal system play a crucial role in the pathology of neurodegenerative LSDs [ 154 ].…”

Coordinating activation of endo‐lysosomal two‐pore channels and TRP mucolipins

“…Recent work has shown that activating TPC2 with TPC2‐A1‐P can revert lysosomal defects in MLIV and other lysosomal storage disorders (Prat Castro et al., 2022; Scotto Rosato et al., 2022). This was ascribed to enhanced lysosomal exocytosis because TPC2‐A1‐P but not TPC2‐A1‐N had previously been shown to boost lysosomal exocytosis (Gerndt et al., 2020).…”