EMBO Molecular Medicine (Sep 2022)
TPC2 rescues lysosomal storage in mucolipidosis type IV, Niemann–Pick type C1, and Batten disease
- Anna Scotto Rosato,
- Einar K Krogsaeter,
- Dawid Jaślan,
- Carla Abrahamian,
- Sandro Montefusco,
- Chiara Soldati,
- Barbara Spix,
- Maria Teresa Pizzo,
- Giuseppina Grieco,
- Julia Böck,
- Amanda Wyatt,
- Daniela Wünkhaus,
- 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
Affiliations
- Anna Scotto Rosato
- Faculty of Medicine, Walther Straub Institute of Pharmacology and Toxicology Ludwig‐Maximilians‐Universität Munich Germany
- Einar K Krogsaeter
- Faculty of Medicine, Walther Straub Institute of Pharmacology and Toxicology Ludwig‐Maximilians‐Universität Munich Germany
- Dawid Jaślan
- Faculty of Medicine, Walther Straub Institute of Pharmacology and Toxicology Ludwig‐Maximilians‐Universität Munich Germany
- Carla Abrahamian
- Faculty of Medicine, Walther Straub Institute of Pharmacology and Toxicology Ludwig‐Maximilians‐Universität Munich Germany
- Sandro Montefusco
- Telethon Institute of Genetics and Medicine Naples Italy
- Chiara Soldati
- Telethon Institute of Genetics and Medicine Naples Italy
- Barbara Spix
- Faculty of Medicine, Walther Straub Institute of Pharmacology and Toxicology Ludwig‐Maximilians‐Universität Munich Germany
- Maria Teresa Pizzo
- Telethon Institute of Genetics and Medicine Naples Italy
- Giuseppina Grieco
- Telethon Institute of Genetics and Medicine Naples Italy
- Julia Böck
- Faculty of Medicine, Walther Straub Institute of Pharmacology and Toxicology Ludwig‐Maximilians‐Universität Munich Germany
- Amanda Wyatt
- Experimental Pharmacology, Center for Molecular Signaling (PZMS) Saarland University School of Medicine Homburg Germany
- Daniela Wünkhaus
- Evotec AG Hamburg Germany
- Marcel Passon
- Faculty of Medicine, Walther Straub Institute of Pharmacology and Toxicology Ludwig‐Maximilians‐Universität Munich Germany
- Marc Stieglitz
- Department of Pharmacy, Center for Drug Research Ludwig‐Maximilians‐Universität Munich Germany
- Marco Keller
- Department of Pharmacy, Center for Drug Research Ludwig‐Maximilians‐Universität Munich Germany
- Guido Hermey
- Center for Molecular Neurobiology Hamburg (ZMNH) Institute of Molecular and Cellular Cognition, UKE Hamburg Germany
- Sandra Markmann
- Evotec AG Hamburg Germany
- Doris Gruber‐Schoffnegger
- Evotec AG Hamburg Germany
- Susan Cotman
- Department of Neurology, Center for Genomic Medicine Massachusetts General Hospital, Harvard Medical School Boston MA USA
- Ludger Johannes
- Cellular and Chemical Biology Department, Institut Curie U1143 INSERM, UMR3666 CNRS, PSL Research University Paris France
- Dennis Crusius
- Institute for Stroke and Dementia Research (ISD) Ludwig‐Maximilians‐University (LMU) Hospital Munich Germany
- Ulrich Boehm
- Experimental Pharmacology, Center for Molecular Signaling (PZMS) Saarland University School of Medicine Homburg Germany
- Christian Wahl‐Schott
- Institute for Neurophysiology Hannover Medical School Hannover Germany
- Martin Biel
- Department of Pharmacy, Center for Drug Research Ludwig‐Maximilians‐Universität Munich Germany
- Franz Bracher
- Department of Pharmacy, Center for Drug Research Ludwig‐Maximilians‐Universität Munich Germany
- Elvira De Leonibus
- Telethon Institute of Genetics and Medicine Naples Italy
- Elena Polishchuk
- Telethon Institute of Genetics and Medicine Naples Italy
- Diego L Medina
- Telethon Institute of Genetics and Medicine Naples Italy
- Dominik Paquet
- Institute for Stroke and Dementia Research (ISD) Ludwig‐Maximilians‐University (LMU) Hospital Munich Germany
- Christian Grimm
- Faculty of Medicine, Walther Straub Institute of Pharmacology and Toxicology Ludwig‐Maximilians‐Universität Munich Germany
- DOI
- https://doi.org/10.15252/emmm.202115377
- Journal volume & issue
-
Vol. 14,
no. 9
pp. n/a – n/a
Abstract
Abstract 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.
Keywords