TPC2 rescues lysosomal storage in mucolipidosis type IV, Niemann-Pick type C1, and Batten disease
Standard
TPC2 rescues lysosomal storage in mucolipidosis type IV, Niemann-Pick type C1, and Batten disease. / Scotto Rosato, Anna; Krogsaeter, Einar K; Jaślan, Dawid; Abrahamian, Carla; Montefusco, Sandro; Soldati, Chiara; Spix, Barbara; Pizzo, Maria Teresa; Grieco, Giuseppina; Böck, Julia; Wyatt, Amanda; Wünkhaus, Daniela; Passon, Marcel; Stieglitz, Marc; Keller, Marco; Hermey, Guido; Gruber-Schoffnegger, Doris; Cotman, Susan; Johannes, Ludger; Crusius, Dennis; Wahl-Schott, Christian; Biel, Martin; Bracher, Franz; De Leonibus, Elvira; Polishchuk, Elena; Medina, Diego L; Paquet, Dominik; Grimm, Christian.
in: EMBO MOL MED, Jahrgang 14, Nr. 9, e15377, 07.09.2022.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
Harvard
APA
Vancouver
Bibtex
}
RIS
TY - JOUR
T1 - TPC2 rescues lysosomal storage in mucolipidosis type IV, Niemann-Pick type C1, and Batten disease
AU - Scotto Rosato, Anna
AU - Krogsaeter, Einar K
AU - Jaślan, Dawid
AU - Abrahamian, Carla
AU - Montefusco, Sandro
AU - Soldati, Chiara
AU - Spix, Barbara
AU - Pizzo, Maria Teresa
AU - Grieco, Giuseppina
AU - Böck, Julia
AU - Wyatt, Amanda
AU - Wünkhaus, Daniela
AU - Passon, Marcel
AU - Stieglitz, Marc
AU - Keller, Marco
AU - Hermey, Guido
AU - Gruber-Schoffnegger, Doris
AU - Cotman, Susan
AU - Johannes, Ludger
AU - Crusius, Dennis
AU - Wahl-Schott, Christian
AU - Biel, Martin
AU - Bracher, Franz
AU - De Leonibus, Elvira
AU - Polishchuk, Elena
AU - Medina, Diego L
AU - Paquet, Dominik
AU - Grimm, Christian
N1 - © 2022 The Authors. Published under the terms of the CC BY 4.0 license.
PY - 2022/9/7
Y1 - 2022/9/7
N2 - 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.
AB - 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.
U2 - 10.15252/emmm.202115377
DO - 10.15252/emmm.202115377
M3 - SCORING: Journal article
C2 - 35929194
VL - 14
JO - EMBO MOL MED
JF - EMBO MOL MED
SN - 1757-4676
IS - 9
M1 - e15377
ER -