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Endocytosis is essential for the cell to adapt to its surrounding environment, and a tight regulation of the endocytic mechanisms is required to maintain cell function and survival. This is particularly significant in the central nervous system (CNS), where composition of neuronal cell surface is crucial for synaptic functioning. In fact, distinct pathologies of the CNS are tightly linked to abnormal endolysosomal function, and several genome wide association analysis (GWAS) and biochemical studies have identified intracellular trafficking regulators as genetic risk factors for such pathologies. The sorting nexins (SNXs) are a family of proteins involved in protein trafficking regulation and signaling. SNXs dysregulation occurs in patients with Alzheimer\u2019s disease (AD), Down\u2019s syndrome (DS), schizophrenia, ataxia and epilepsy, among others, establishing clear roles for this protein family in pathology. Interestingly, restoration of SNXs levels has been shown to trigger synaptic plasticity recovery in a DS mouse model. This review encompasses an historical and evolutionary overview of SNXs protein family, focusing on its organization, phyla conservation, and evolution throughout the development of the nervous system during speciation. We will also survey SNXs molecular interactions and highlight how defects on SNXs underlie distinct pathologies of the CNS. Ultimately, we discuss possible strategies of intervention, surveying how our knowledge about the fundamental processes regulated by SNXs can be applied to the identification of novel therapeutic avenues for SNXs-related disorders.<\/jats:p>","DOI":"10.1007\/s12035-021-02388-9","type":"journal-article","created":{"date-parts":[[2021,5,3]],"date-time":"2021-05-03T12:29:50Z","timestamp":1620044990000},"page":"4070-4106","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":36,"title":["Sorting Out Sorting Nexins Functions in the Nervous System in Health and Disease"],"prefix":"10.1007","volume":"58","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7166-4336","authenticated-orcid":false,"given":"Neide","family":"Vieira","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8374-6347","authenticated-orcid":false,"given":"Teresa","family":"Rito","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2202-5431","authenticated-orcid":false,"given":"Margarida","family":"Correia-Neves","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8755-5126","authenticated-orcid":false,"given":"Nuno","family":"Sousa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,5,1]]},"reference":[{"issue":"7","key":"2388_CR1","doi-asserted-by":"publisher","first-page":"574","DOI":"10.1038\/nrm2427","volume":"9","author":"PJ Cullen","year":"2008","unstructured":"Cullen PJ (2008) Endosomal sorting and signalling: an emerging role for sorting nexins. 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