Genistein activates transcription factor EB and corrects Niemann–Pick C phenotype

Argüello-Florencio, Graciela R.; Balboa, Elisa; Castro, Juan; Yañez, María José; Mattar, Pamela; Pulgar, Rodrigo; Zanlungo, Silvana; Tapia, Pablo J.

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dc.contributor.author	Argüello-Florencio, Graciela R.
dc.contributor.author	Balboa, Elisa
dc.contributor.author	Castro, Juan
dc.contributor.author	Yañez, María José
dc.contributor.author	Mattar, Pamela
dc.contributor.author	Pulgar, Rodrigo
dc.contributor.author	Zanlungo, Silvana
dc.contributor.author	Tapia, Pablo J.
dc.date.accessioned	2021-12-21T13:10:49Z
dc.date.available	2021-12-21T13:10:49Z
dc.date.issued	2021
dc.identifier.uri	http://repositorio.ucm.cl/handle/ucm/3645
dc.description.abstract	Niemann–Pick type C disease (NPCD) is a lysosomal storage disease (LSD) characterized by abnormal cholesterol accumulation in lysosomes, impaired autophagy flux, and lysosomal dysfunction. The activation of transcription factor EB (TFEB), a master lysosomal function regulator, reduces the accumulation of lysosomal substrates in LSDs where the degradative capacity of the cells is compromised. Genistein can pass the blood–brain barrier and activate TFEB. Hence, we investigated the effect of TFEB activation by genistein toward correcting the NPC phenotype. We show that genistein promotes TFEB translocation to the nucleus in HeLa TFEB-GFP, Huh7, and SHSY-5Y cells treated with U18666A and NPC1 patient fibroblasts. Genistein treatment improved lysosomal protein expression and autophagic flux, decreasing p62 levels and increasing those of the LC3-II in NPC1 patient fibroblasts. Genistein induced an increase in β-hexosaminidase activity in the culture media of NPC1 patient fibroblasts, suggesting an increase in lysosomal exocytosis, which correlated with a decrease in cholesterol accumulation after filipin staining, including cells treated with U18666A and NPC1 patient fibroblasts. These results support that genistein-mediated TFEB activation corrects pathological phenotypes in NPC models and substantiates the need for further studies on this isoflavonoid as a potential therapeutic agent to treat NPCD and other LSDs with neurological compromise.	es_CL
dc.language.iso	en	es_CL
dc.rights	Atribución-NoComercial-SinDerivadas 3.0 Chile	*
dc.rights.uri	http://creativecommons.org/licenses/by-nc-nd/3.0/cl/	*
dc.source	International Journal of Molecular Sciences, 22(8), 4220	es_CL
dc.subject	Niemann–Pick C	es_CL
dc.subject	Genistein	es_CL
dc.subject	Lysosomal storage diseases	es_CL
dc.subject	Cholesterol	es_CL
dc.subject	Lysosome clearance	es_CL
dc.title	Genistein activates transcription factor EB and corrects Niemann–Pick C phenotype	es_CL
dc.type	Article	es_CL
dc.ucm.facultad	Facultad de Ciencias de la Salud	es_CL
dc.ucm.indexacion	Scopus	es_CL
dc.ucm.indexacion	Isi	es_CL
dc.ucm.uri	www.mdpi.com/1422-0067/22/8/4220	es_CL
dc.ucm.doi	doi.org/10.3390/ijms22084220	es_CL