TRPML1 activation ameliorates lysosomal phenotypes in CLN3 deficient retinal pigment epithelial cells
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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, Vol. 14, No. 1, 17469, 29.07.2024.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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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
N1 - © 2024. The Author(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 -