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Orphan receptors, a class of receptors with no known endogenous ligands, emerge as promising druggable targets for diverse diseases. This review aims to direct attention to a subgroup of orphan GPCRs, in particular class A orphans that have roles in neurodegenerative disorders, including Alzheimer\u2019s disease, Parkinson\u2019s disease, Huntington\u2019s disease, and Multiple sclerosis. We highlight the diverse roles orphan receptors play in regulating critical cellular processes such as synaptic transmission, neuronal survival and neuro-inflammation. Moreover, we discuss the therapeutic potential of targeting orphan receptors for the treatment of neurodegenerative disorders, emphasizing recent advances in drug discovery and preclinical studies. Finally, we outline future directions and challenges in orphan receptor research.<\/jats:p>","DOI":"10.3389\/fphar.2024.1394516","type":"journal-article","created":{"date-parts":[[2024,6,4]],"date-time":"2024-06-04T05:40:22Z","timestamp":1717479622000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":20,"title":["Exploring orphan GPCRs in neurodegenerative diseases"],"prefix":"10.3389","volume":"15","author":[{"given":"Devrim","family":"\u00d6z-Arslan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melis","family":"Yavuz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beki","family":"Kan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2024,6,4]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"5524","DOI":"10.3390\/ijms24065524","article-title":"The mechanisms of GPR55 receptor functional selectivity during apoptosis and proliferation regulation in cancer cells","volume":"24","author":"Akimov","year":"2023","journal-title":"Int. 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