TRPML1 activation ameliorates lysosomal phenotypes in CLN3 deficient retinal pigment epithelial cells

D Wünkhaus; R Tang; K Nyame; N N Laqtom; M Schweizer; A Scotto Rosato; E K Krogsæter; C Wollnik; M Abu-Remaileh; C Grimm; G Hermey; R Kuhn; D Gruber-Schoffnegger; S Markmann

doi:10.1038/s41598-024-67479-8

TRPML1 activation ameliorates lysosomal phenotypes in CLN3 deficient retinal pigment epithelial cells

Standard

TRPML1 activation ameliorates lysosomal phenotypes in CLN3 deficient retinal pigment epithelial cells. / Wünkhaus, D; Tang, R; Nyame, K; Laqtom, N N; Schweizer, M; Scotto Rosato, A; Krogsæter, E K; Wollnik, C; Abu-Remaileh, M; Grimm, C; Hermey, G; Kuhn, R; Gruber-Schoffnegger, D; Markmann, S.

in: SCI REP-UK, Jahrgang 14, Nr. 1, 17469, 29.07.2024.

Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung

Harvard

Wünkhaus, D, Tang, R, Nyame, K, Laqtom, NN, Schweizer, M, Scotto Rosato, A, Krogsæter, EK, Wollnik, C, Abu-Remaileh, M, Grimm, C, Hermey, G, Kuhn, R, Gruber-Schoffnegger, D & Markmann, S 2024, 'TRPML1 activation ameliorates lysosomal phenotypes in CLN3 deficient retinal pigment epithelial cells', SCI REP-UK, Jg. 14, Nr. 1, 17469. https://doi.org/10.1038/s41598-024-67479-8

APA

Wünkhaus, D., Tang, R., Nyame, K., Laqtom, N. N., Schweizer, M., Scotto Rosato, A., Krogsæter, E. K., Wollnik, C., Abu-Remaileh, M., Grimm, C., Hermey, G., Kuhn, R., Gruber-Schoffnegger, D., & Markmann, S. (2024). TRPML1 activation ameliorates lysosomal phenotypes in CLN3 deficient retinal pigment epithelial cells. SCI REP-UK, 14(1), [17469]. https://doi.org/10.1038/s41598-024-67479-8

Vancouver

Wünkhaus D, Tang R, Nyame K, Laqtom NN, Schweizer M, Scotto Rosato A et al. TRPML1 activation ameliorates lysosomal phenotypes in CLN3 deficient retinal pigment epithelial cells. SCI REP-UK. 2024 Jul 29;14(1). 17469. https://doi.org/10.1038/s41598-024-67479-8

Bibtex

@article{95e2125b43ef433883dade93088f2f98,

title = "TRPML1 activation ameliorates lysosomal phenotypes in CLN3 deficient retinal pigment epithelial cells",

abstract = "Mutations in the lysosomal membrane protein CLN3 cause Juvenile Neuronal Ceroid Lipofuscinosis (JNCL). Activation of the lysosomal ion channel TRPML1 has previously been shown to be beneficial in several neurodegenerative disease models. Here, we tested whether TRPML1 activation rescues disease-associated phenotypes in CLN3-deficient retinal pigment epithelial (ARPE-19 CLN3-KO) cells. ARPE-19 CLN3-KO cells accumulate LAMP1 positive organelles and show lysosomal storage of mitochondrial ATPase subunit C (SubC), globotriaosylceramide (Gb3), and glycerophosphodiesters (GPDs), whereas lysosomal bis(monoacylglycero)phosphate (BMP/LBPA) lipid levels were significantly decreased. Activation of TRPML1 reduced lysosomal storage of Gb3 and SubC but failed to restore BMP levels in CLN3-KO cells. TRPML1-mediated decrease of storage was TFEB-independent, and we identified TRPML1-mediated enhanced lysosomal exocytosis as a likely mechanism for clearing storage including GPDs. Therefore, ARPE-19 CLN3-KO cells represent a human cell model for CLN3 disease showing many of the described core lysosomal deficits, some of which can be improved using TRPML1 agonists.",

keywords = "Lysosomes/metabolism, Humans, Retinal Pigment Epithelium/metabolism, Molecular Chaperones/metabolism, Membrane Glycoproteins/metabolism, Neuronal Ceroid-Lipofuscinoses/metabolism, Transient Receptor Potential Channels/metabolism, Phenotype, Cell Line, Exocytosis, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/metabolism, Lysophospholipids, Monoglycerides",

author = "D W{\"u}nkhaus and R Tang and K Nyame and Laqtom, {N N} and M Schweizer and {Scotto Rosato}, A and Krogs{\ae}ter, {E K} and C Wollnik and M Abu-Remaileh and C Grimm and G Hermey and R Kuhn and D Gruber-Schoffnegger and S Markmann",

note = "{\textcopyright} 2024. The Author(s).",

year = "2024",

month = jul,

day = "29",

doi = "10.1038/s41598-024-67479-8",

language = "English",

volume = "14",

journal = "SCI REP-UK",

issn = "2045-2322",

publisher = "NATURE PUBLISHING GROUP",

number = "1",

}

RIS

TY - JOUR

T1 - TRPML1 activation ameliorates lysosomal phenotypes in CLN3 deficient retinal pigment epithelial cells

AU - Wünkhaus, D

AU - Tang, R

AU - Nyame, K

AU - Laqtom, N N

AU - Schweizer, M

AU - Scotto Rosato, A

AU - Krogsæter, E K

AU - Wollnik, C

AU - Abu-Remaileh, M

AU - Grimm, C

AU - Hermey, G

AU - Kuhn, R

AU - Gruber-Schoffnegger, D

AU - Markmann, S

PY - 2024/7/29

Y1 - 2024/7/29

N2 - Mutations in the lysosomal membrane protein CLN3 cause Juvenile Neuronal Ceroid Lipofuscinosis (JNCL). Activation of the lysosomal ion channel TRPML1 has previously been shown to be beneficial in several neurodegenerative disease models. Here, we tested whether TRPML1 activation rescues disease-associated phenotypes in CLN3-deficient retinal pigment epithelial (ARPE-19 CLN3-KO) cells. ARPE-19 CLN3-KO cells accumulate LAMP1 positive organelles and show lysosomal storage of mitochondrial ATPase subunit C (SubC), globotriaosylceramide (Gb3), and glycerophosphodiesters (GPDs), whereas lysosomal bis(monoacylglycero)phosphate (BMP/LBPA) lipid levels were significantly decreased. Activation of TRPML1 reduced lysosomal storage of Gb3 and SubC but failed to restore BMP levels in CLN3-KO cells. TRPML1-mediated decrease of storage was TFEB-independent, and we identified TRPML1-mediated enhanced lysosomal exocytosis as a likely mechanism for clearing storage including GPDs. Therefore, ARPE-19 CLN3-KO cells represent a human cell model for CLN3 disease showing many of the described core lysosomal deficits, some of which can be improved using TRPML1 agonists.

AB - Mutations in the lysosomal membrane protein CLN3 cause Juvenile Neuronal Ceroid Lipofuscinosis (JNCL). Activation of the lysosomal ion channel TRPML1 has previously been shown to be beneficial in several neurodegenerative disease models. Here, we tested whether TRPML1 activation rescues disease-associated phenotypes in CLN3-deficient retinal pigment epithelial (ARPE-19 CLN3-KO) cells. ARPE-19 CLN3-KO cells accumulate LAMP1 positive organelles and show lysosomal storage of mitochondrial ATPase subunit C (SubC), globotriaosylceramide (Gb3), and glycerophosphodiesters (GPDs), whereas lysosomal bis(monoacylglycero)phosphate (BMP/LBPA) lipid levels were significantly decreased. Activation of TRPML1 reduced lysosomal storage of Gb3 and SubC but failed to restore BMP levels in CLN3-KO cells. TRPML1-mediated decrease of storage was TFEB-independent, and we identified TRPML1-mediated enhanced lysosomal exocytosis as a likely mechanism for clearing storage including GPDs. Therefore, ARPE-19 CLN3-KO cells represent a human cell model for CLN3 disease showing many of the described core lysosomal deficits, some of which can be improved using TRPML1 agonists.

KW - Lysosomes/metabolism

KW - Humans

KW - Retinal Pigment Epithelium/metabolism

KW - Molecular Chaperones/metabolism

KW - Membrane Glycoproteins/metabolism

KW - Neuronal Ceroid-Lipofuscinoses/metabolism

KW - Transient Receptor Potential Channels/metabolism

KW - Phenotype

KW - Cell Line

KW - Exocytosis

KW - Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/metabolism

KW - Lysophospholipids

KW - Monoglycerides

U2 - 10.1038/s41598-024-67479-8

DO - 10.1038/s41598-024-67479-8

M3 - SCORING: Journal article

C2 - 39080379

VL - 14

JO - SCI REP-UK

JF - SCI REP-UK

SN - 2045-2322

IS - 1

M1 - 17469

ER -