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The progressive cellular buildup of the highly reactive intermediate 3,4-dihydroxyphenylacetaldehye (DOPAL) generates protein cross-linking, oligomerization of the PD-linked \u03b1Synuclein (\u03b1Syn) and imbalance in protein quality control. In this scenario, the autophagic cargo sequestome-1 (SQSTM1\/p62) emerges as a target of DOPAL-dependent oligomerization and accumulation in cytosolic clusters. Although DOPAL-induced oxidative stress and activation of the Nrf2 pathway promote p62 expression, p62 oligomerization rather seems to be a consequence of direct DOPAL modification. DOPAL-induced p62 clusters are positive for ubiquitin and accumulate within lysosomal-related structures, likely affecting the autophagy-lysosomal functionality. Finally, p62 oligomerization and clustering is synergistically augmented by DOPAL-induced \u03b1Syn buildup. Hence, the substantial impact on p62 proteostasis caused by DOPAL appears of relevance for dopaminergic neurodegeneration, in which the progressive failure of degradative pathways and the deposition of proteins like \u03b1Syn, ubiquitin and p62 in inclusion bodies represent a major trait of PD pathology.<\/jats:p>","DOI":"10.1038\/s41419-024-06763-x","type":"journal-article","created":{"date-parts":[[2024,6,18]],"date-time":"2024-06-18T05:02:47Z","timestamp":1718686967000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Sequestosome-1 (SQSTM1\/p62) as a target in dopamine catabolite-mediated cellular dyshomeostasis"],"prefix":"10.1038","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4450-1838","authenticated-orcid":false,"given":"Anna","family":"Masato","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0566-2391","authenticated-orcid":false,"given":"Annapaola","family":"Andolfo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-2397-9218","authenticated-orcid":false,"given":"Giulia","family":"Favetta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9766-7685","authenticated-orcid":false,"given":"Edoardo Niccol\u00f2","family":"Bellini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susanna","family":"Cogo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8097-6369","authenticated-orcid":false,"given":"Luisa","family":"Dalla Valle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela","family":"Boassa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8172-3598","authenticated-orcid":false,"given":"Elisa","family":"Greggio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicoletta","family":"Plotegher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7927-9208","authenticated-orcid":false,"given":"Luigi","family":"Bubacco","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,6,18]]},"reference":[{"key":"6763_CR1","doi-asserted-by":"publisher","first-page":"S3","DOI":"10.3233\/JPD-181474","volume":"8","author":"ER Dorsey","year":"2018","unstructured":"Dorsey ER, Sherer T, Okun MS, Bloemd BR. 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