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

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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, Vol. 14, No. 9, e15377, 07.09.2022.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Scotto Rosato, A, Krogsaeter, EK, Jaślan, D, Abrahamian, C, Montefusco, S, Soldati, C, Spix, B, Pizzo, MT, Grieco, G, Böck, J, Wyatt, A, Wünkhaus, D, Passon, M, Stieglitz, M, Keller, M, Hermey, G, Gruber-Schoffnegger, D, Cotman, S, Johannes, L, Crusius, D, Wahl-Schott, C, Biel, M, Bracher, F, De Leonibus, E, Polishchuk, E, Medina, DL, Paquet, D & Grimm, C 2022, 'TPC2 rescues lysosomal storage in mucolipidosis type IV, Niemann-Pick type C1, and Batten disease', EMBO MOL MED, vol. 14, no. 9, e15377. https://doi.org/10.15252/emmm.202115377

APA

Scotto Rosato, A., Krogsaeter, E. K., Jaślan, D., Abrahamian, C., Montefusco, S., Soldati, C., Spix, B., Pizzo, M. T., Grieco, G., Böck, J., Wyatt, A., Wünkhaus, D., Passon, M., Stieglitz, M., Keller, M., Hermey, G., Gruber-Schoffnegger, D., Cotman, S., Johannes, L., ... Grimm, C. (2022). TPC2 rescues lysosomal storage in mucolipidosis type IV, Niemann-Pick type C1, and Batten disease. EMBO MOL MED, 14(9), [e15377]. https://doi.org/10.15252/emmm.202115377

Vancouver

Scotto Rosato A, Krogsaeter EK, Jaślan D, Abrahamian C, Montefusco S, Soldati C et al. TPC2 rescues lysosomal storage in mucolipidosis type IV, Niemann-Pick type C1, and Batten disease. EMBO MOL MED. 2022 Sep 7;14(9). e15377. https://doi.org/10.15252/emmm.202115377

Bibtex

@article{0977d1a00db6488e9a331687523de96a,
title = "TPC2 rescues lysosomal storage in mucolipidosis type IV, Niemann-Pick type C1, and Batten disease",
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.",
author = "{Scotto Rosato}, Anna and Krogsaeter, {Einar K} and Dawid Ja{\'s}lan and Carla Abrahamian and Sandro Montefusco and Chiara Soldati and Barbara Spix and Pizzo, {Maria Teresa} and Giuseppina Grieco and Julia B{\"o}ck and Amanda Wyatt and Daniela W{\"u}nkhaus and Marcel Passon and Marc Stieglitz and Marco Keller and Guido Hermey and Doris Gruber-Schoffnegger and Susan Cotman and Ludger Johannes and Dennis Crusius and Christian Wahl-Schott and Martin Biel and Franz Bracher and {De Leonibus}, Elvira and Elena Polishchuk and Medina, {Diego L} and Dominik Paquet and Christian Grimm",
note = "{\textcopyright} 2022 The Authors. Published under the terms of the CC BY 4.0 license.",
year = "2022",
month = sep,
day = "7",
doi = "10.15252/emmm.202115377",
language = "English",
volume = "14",
journal = "EMBO MOL MED",
issn = "1757-4676",
publisher = "Wiley-Blackwell",
number = "9",

}

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 -