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This concept, which is often overlooked, may play a role in synucleinopathies such as Parkinson's disease (PD), and dementia with Lewy bodies (DLB), where the protein \u03b1\u2010synuclein (aSyn) is known to accumulate in insoluble inclusions. aSyn is at the crossroads between cellular proteostasis and lipidostasis networks and, therefore, we must be aware of the complexity we face when we try to understand the molecular basis of synucleinopathies. Importantly, aSyn and \u03b2\u2010glucocerebrosidase (GCase), a sphingolipid hydrolase also strongly implicated in PD and DLB, are connected to lipid biology and to protein quality control function. Thus, changes in the normal relationship between these two proteins may shift the balance in the cell and lead to proteinopathy and\/or proteinopenia, while also affecting lipidostasis of cells in the brain. Thus, pathological mechanisms that are a consequence of (a) loss\u2010of\u2010function, (b) gain\u2010of\u2010toxic function, and (c) alterations in lipidostasis need to be carefully analyzed and integrated in our study of the molecular underpinnings of neurodegenerative mechanisms. Here, we highlight implications of the depletion of the soluble form of aSyn, and of GCase, and discuss how state\u2010of\u2010the\u2010art \u2018omics technologies\u2019 could be deployed to assist in the clinical assessment of synucleinopathies.<\/jats:p>","DOI":"10.1111\/febs.70011","type":"journal-article","created":{"date-parts":[[2025,3,8]],"date-time":"2025-03-08T18:55:21Z","timestamp":1741460121000},"page":"4774-4788","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Expanding our understanding of synucleinopathies: proteinopathy, proteinopenia, and lipidopathy"],"prefix":"10.1111","volume":"292","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1094-8773","authenticated-orcid":false,"given":"Manuel","family":"Flores\u2010Le\u00f3n","sequence":"first","affiliation":[{"name":"Department of Experimental Neurodegeneration, Center for Biostructural Imaging of Neurodegeneration University Medical Center 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