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HEALITALIA","award":["2020\/08840-1"],"award-info":[{"award-number":["2020\/08840-1"]}]},{"name":"Ministry of University Program HEALITALIA","award":["2016\/20796-2"],"award-info":[{"award-number":["2016\/20796-2"]}]},{"name":"Ministry of University Program HEALITALIA","award":["001"],"award-info":[{"award-number":["001"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Huntington\u2019s disease (HD) is a progressive neurodegenerative disease characterized by mutations in the huntingtin gene (mHtt), causing an unstable repeat of the CAG trinucleotide, leading to abnormal long repeats of polyglutamine (poly-Q) in the N-terminal region of the huntingtin, which form abnormal conformations and aggregates. Alterations in Ca2+ signaling are involved in HD models and the accumulation of mutated huntingtin interferes with Ca2+ homeostasis. Lysosomes are intracellular Ca2+ storages that participate in endocytic and lysosomal degradation processes, including autophagy. Nicotinic acid adenine dinucleotide phosphate (NAADP) is an intracellular second messenger that promotes Ca2+ release from the endo-lysosomal system via Two-Pore Channels (TPCs) activation. Herein, we show the impact of lysosomal Ca2+ signals on mHtt aggregation and autophagy blockade in murine astrocytes overexpressing mHtt-Q74. We observed that mHtt-Q74 overexpression causes an increase in NAADP-evoked Ca2+ signals and mHtt aggregation, which was inhibited in the presence of Ned-19, a TPC antagonist, or BAPTA-AM, a Ca2+ chelator. Additionally, TPC2 silencing revert the mHtt aggregation. Furthermore, mHtt has been shown co-localized with TPC2 which may contribute to its effects on lysosomal homeostasis. Moreover, NAADP-mediated autophagy was also blocked since its function is dependent on lysosomal functionality. Taken together, our data show that increased levels of cytosolic Ca2+ mediated by NAADP causes mHtt aggregation. Additionally, mHtt co-localizes with the lysosomes, where it possibly affects organelle functions and impairs autophagy.<\/jats:p>","DOI":"10.3390\/ijms24065593","type":"journal-article","created":{"date-parts":[[2023,3,15]],"date-time":"2023-03-15T05:53:44Z","timestamp":1678859624000},"page":"5593","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["NAADP-Evoked Ca2+ Signaling Leads to Mutant Huntingtin Aggregation and Autophagy Impairment in Murine Astrocytes"],"prefix":"10.3390","volume":"24","author":[{"given":"C\u00e1ssia Arruda de Souza","family":"Pereira","sequence":"first","affiliation":[{"name":"Departament of Pharmacology, Escola Paulista de Medicina, Universidade Federal de S\u00e3o Paulo, S\u00e3o Paulo 04044-020, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalia de Castro","family":"Medaglia","sequence":"additional","affiliation":[{"name":"Departament of Pharmacology, Escola Paulista de Medicina, Universidade Federal de S\u00e3o Paulo, S\u00e3o Paulo 04044-020, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3371-3376","authenticated-orcid":false,"given":"Rodrigo Portes","family":"Ureshino","sequence":"additional","affiliation":[{"name":"Instituto de Ci\u00eancias Ambientais, Qu\u00edmicas e Farmac\u00eauticas, Universidade Federal de S\u00e3o Paulo, Diadema 09913-030, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6666-3673","authenticated-orcid":false,"given":"Claudia","family":"Bincoletto","sequence":"additional","affiliation":[{"name":"Departament of Pharmacology, Escola Paulista de Medicina, Universidade Federal de S\u00e3o Paulo, S\u00e3o Paulo 04044-020, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7568-4713","authenticated-orcid":false,"given":"Manuela","family":"Antonioli","sequence":"additional","affiliation":[{"name":"Department of Epidemiology, Preclinical Research and Advanced Diagnostics, National Institute for Infectious Diseases IRCCS \u201cL. Spallanzani\u201d, 00149 Rome, Italy"},{"name":"Department of Biology, University of Rome \u201cTor Vergata\u201d, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4438-3325","authenticated-orcid":false,"given":"Gian Maria","family":"Fimia","sequence":"additional","affiliation":[{"name":"Department of Epidemiology, Preclinical Research and Advanced Diagnostics, National Institute for Infectious Diseases IRCCS \u201cL. Spallanzani\u201d, 00149 Rome, Italy"},{"name":"Department of Molecular Medicine, University of Rome \u201cSapienza\u201d, 00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mauro","family":"Piacentini","sequence":"additional","affiliation":[{"name":"Department of Epidemiology, Preclinical Research and Advanced Diagnostics, National Institute for Infectious Diseases IRCCS \u201cL. Spallanzani\u201d, 00149 Rome, Italy"},{"name":"Department of Biology, University of Rome \u201cTor Vergata\u201d, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6765-1276","authenticated-orcid":false,"given":"Gustavo Jos\u00e9 da Silva","family":"Pereira","sequence":"additional","affiliation":[{"name":"Departament of Pharmacology, Escola Paulista de Medicina, Universidade Federal de S\u00e3o Paulo, S\u00e3o Paulo 04044-020, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1903-4150","authenticated-orcid":false,"given":"Adolfo Garcia","family":"Erustes","sequence":"additional","affiliation":[{"name":"Departament of Pharmacology, Escola Paulista de Medicina, Universidade Federal de S\u00e3o Paulo, S\u00e3o Paulo 04044-020, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5844-1368","authenticated-orcid":false,"given":"Soraya Soubhi","family":"Smaili","sequence":"additional","affiliation":[{"name":"Departament of Pharmacology, Escola Paulista de Medicina, Universidade Federal de S\u00e3o Paulo, S\u00e3o Paulo 04044-020, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,3,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1083","DOI":"10.1002\/mds.25075","article-title":"The incidence and prevalence of Huntington\u2019s disease: A systematic review and meta-analysis","volume":"27","author":"Pringsheim","year":"2012","journal-title":"Mov. 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