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In the brain, these substrates accumulate in the lysosomes of neurons and glial cells, leading to neuroinflammation and neurodegeneration. Their storage also affects lysosomal homeostasis-inducing activity of several lysosomal proteases including cathepsin B (CATB). In the central nervous system, increased CATB activity has been associated with the deposition of amyloid plaques due to an alternative pro-amyloidogenic processing of the amyloid precursor protein (APP), suggesting a potential role of this enzyme in the neuropathology of MPS I. In this study, we report elevated levels of protein expression and activity of CATB in cortex tissues of 6-month-old MPS I (Idua -\/- mice. Besides, increased CATB leakage from lysosomes to the cytoplasm of Idua -\/- cortical pyramidal neurons was indicative of damaged lysosomal membranes. The increased CATB activity coincided with an elevated level of the 16-kDa C-terminal APP fragment, which together with unchanged levels of \u03b2-secretase 1 was suggestive for the role of this enzyme in the amyloidogenic APP processing. Neuronal accumulation of Thioflavin-S-positive misfolded protein aggregates and drastically increased levels of neuroinflammatory glial fibrillary acidic protein (GFAP)-positive astrocytes and CD11b-positive activated microglia were observed in Idua -\/- cortex by confocal fluorescent microscopy. Together, our results point to the existence of a novel CATB-associated alternative amyloidogenic pathway in MPS I brain induced by lysosomal storage and potentially leading to neurodegeneration.<\/jats:p>","DOI":"10.3390\/ijms21041459","type":"journal-article","created":{"date-parts":[[2020,2,21]],"date-time":"2020-02-21T08:59:47Z","timestamp":1582275587000},"page":"1459","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Cathepsin B-associated Activation of Amyloidogenic Pathway in Murine Mucopolysaccharidosis Type I Brain Cortex"],"prefix":"10.3390","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0473-9665","authenticated-orcid":false,"given":"Gustavo Monteiro","family":"Viana","sequence":"first","affiliation":[{"name":"Department of Biochemistry, Universidade Federal de S\u00e3o Paulo (UNIFESP), S\u00e3o Paulo, SP 04044-020, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Esteban Alberto","family":"Gonzalez","sequence":"additional","affiliation":[{"name":"Gene Therapy Center, Hospital de Cl\u00ednicas de Porto Alegre, Porto Alegre, RS 90035-903, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcela Maciel Palacio","family":"Alvarez","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Universidade Federal de S\u00e3o Paulo (UNIFESP), S\u00e3o Paulo, SP 04044-020, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renan Pelluzzi","family":"Cavalheiro","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Universidade Federal de S\u00e3o Paulo (UNIFESP), S\u00e3o Paulo, SP 04044-020, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cinthia Castro","family":"do Nascimento","sequence":"additional","affiliation":[{"name":"Department of Psychobiology, Universidade Federal de S\u00e3o Paulo (UNIFESP), S\u00e3o Paulo, SP 04024-002, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1598-5861","authenticated-orcid":false,"given":"Guilherme","family":"Baldo","sequence":"additional","affiliation":[{"name":"Gene Therapy Center, Hospital de Cl\u00ednicas de Porto Alegre, Porto Alegre, RS 90035-903, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"V\u00e2nia","family":"D\u2019Almeida","sequence":"additional","affiliation":[{"name":"Department of Psychobiology, Universidade Federal de S\u00e3o Paulo (UNIFESP), S\u00e3o Paulo, SP 04024-002, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcelo Andrade","family":"de Lima","sequence":"additional","affiliation":[{"name":"Molecular &amp; Structural Biosciences, School of Life Sciences, Keele University, Huxley Building, Keele, Staffordshire ST5 5BG, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6612-1062","authenticated-orcid":false,"given":"Alexey V.","family":"Pshezhetsky","sequence":"additional","affiliation":[{"name":"Division of Medical Genetics, CHU Ste-Justine Research Centre, Montreal, QC H3T 1C5, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7569-2166","authenticated-orcid":false,"given":"Helena Bonciani","family":"Nader","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Universidade Federal de S\u00e3o Paulo (UNIFESP), S\u00e3o Paulo, SP 04044-020, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,2,20]]},"reference":[{"key":"ref_1","unstructured":"Neufeld, E.F., and Muenzer, J. 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