TPC2 rescues lysosomal storage in mucolipidosis type IV, Niemann–Pick type C1, and Batten disease

Authors: Anna Scotto Rosato, Einar K Krogsaeter1, Dawid Jaslan, Carla Abrahamian, Sandro Montefusco, Chiara Soldati, Barbara Spix, Maria Teresa Pizzo, Giuseppina Grieco, Julia Böck, Amanda Wyatt, Daniela Wunkhaus, Marcel Passon, Marc Stieglitz, Marco Keller, Guido Hermey, Sandra Markmann, Doris Gruber-Schoffnegger, Susan Cotman, Ludger Johannes, Dennis Crusius, Ulrich Boehm, Christian Wahl-Schott, Martin Biel, Franz Bracher, Elvira De Leonibus, Elena Polishchuk, Diego L Medina, Dominik Paquet & Christian Grimm
Year: 2022
Sources: EMBO Molecular Medicine
Lysosomes are cell organelles that degrade macromolecules to recycle their components. If lysosomal degradative function is impaired, e.g., due to mutations in lysosomal enzymes or membrane proteins, lysosomal storage diseases (LSDs) can develop.
LSDs manifest often with neurodegenerative symptoms, typically starting in early childhood, and going along with a strongly reduced life expectancy and quality of life. We show here that small molecule activation of the Ca2+-permeable endolysosomal
two-pore channel 2 (TPC2) results in an amelioration of cellular phenotypes associated with LSDs such as cholesterol or lipofuscin accumulation, or the formation of abnormal vacuoles seen by electron microscopy. Rescue effects by TPC2 activation, which promotes lysosomal exocytosis and autophagy, were assessed in mucolipidosis type IV (MLIV), Niemann–Pick type C1, and Batten disease patient fibroblasts, and in neurons derived from newly generated isogenic human iPSC models for MLIV and Batten disease. For in vivo proof of concept, we tested TPC2 activation in the MLIV mouse model. In sum, our data suggest that TPC2 is a promising target for the treatment of different types of LSDs, both in vitro and in-vivo.
Category: journals