{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T16:09:39Z","timestamp":1790611779841,"version":"4.1.0"},"reference-count":90,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,4,8]],"date-time":"2026-04-08T00:00:00Z","timestamp":1775606400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003196","name":"Ministry of Health, Italy","doi-asserted-by":"publisher","award":["RRC-2026-23688274"],"award-info":[{"award-number":["RRC-2026-23688274"]}],"id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"publisher"}]},{"award":["RRC-2026-23688274"],"award-info":[{"award-number":["RRC-2026-23688274"]}],"id":[{"id":"https:\/\/ror.org\/00789fa95","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The SH-SY5Y cell line is widely used as an in vitro model for pharmacological and molecular investigations of Parkinson\u2019s disease (PD). The use of SH-SY5Y cells in PD research critically relies on their ability to differentiate into a mature, post-mitotic, dopaminergic (DAergic) neuronal phenotype. However, SH-SY5Y cells are inherently heterogeneous since they are firstly catecholaminergic cells and may express diverse phenotypic markers besides the DAergic ones. These properties seem to be determined by the differentiation protocol that is employed, thus meaning it is crucial to obtain proper cell types. This systematic review aims to discuss the main differentiation protocols used in PD research over the last 30 years. They include inducers such as retinoic acid (RA), the phorbol ester TPA, and the BDNF. Among the 514 studies that were screened, 249 employed these inducers. Then, we quantitatively report the ability of these protocols to differentiate SH-SY5Y cells in mature DAergic neurons, evaluating morphology, differentiation markers, and DAergic markers among the studies that specifically compared differentiated to undifferentiated SH-SY5Y cells (61 studies over 249). As our research shows, despite the highest usage of the RA differentiation protocol, the combination of RA with the BDNF inducer seems to increase the expression and the acquisition of a DAergic phenotype. Nevertheless, during this analysis, some limitations emerged, highlighting the intrinsic phenotypic heterogeneity of these cells, thereby limiting their suitability according to the specific biological question under investigation. A deep investigation into the literature about the molecular phenotypic features of differentiated SH-SY5Y cells may eventually help us to understand the advantages and disadvantages of each protocol that was employed, and adequately set experiments around the PD research.<\/jats:p>","DOI":"10.3390\/ijms27083355","type":"journal-article","created":{"date-parts":[[2026,4,8]],"date-time":"2026-04-08T15:26:39Z","timestamp":1775661999000},"page":"3355","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Dopaminergic Identity of SH-SY5Y Cells Across Differentiation Protocols in Parkinson\u2019s Disease Research: A Systematic Review"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-8771-0317","authenticated-orcid":false,"given":"Osvaldo","family":"Artimagnella","sequence":"first","affiliation":[{"name":"IRCCS Centro Neurolesi \u201cBonino-Pulejo\u201d, Via Provinciale Palermo, Contrada Casazza, 98124 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-4084-6568","authenticated-orcid":false,"given":"Alessia","family":"Floramo","sequence":"additional","affiliation":[{"name":"IRCCS Centro Neurolesi \u201cBonino-Pulejo\u201d, Via Provinciale Palermo, Contrada Casazza, 98124 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0823-1455","authenticated-orcid":false,"given":"Giovanni Luca","family":"Cipriano","sequence":"additional","affiliation":[{"name":"IRCCS Centro Neurolesi \u201cBonino-Pulejo\u201d, Via Provinciale Palermo, Contrada Casazza, 98124 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-9058-5755","authenticated-orcid":false,"given":"Veronica","family":"Argento","sequence":"additional","affiliation":[{"name":"IRCCS Centro Neurolesi \u201cBonino-Pulejo\u201d, Via Provinciale Palermo, Contrada Casazza, 98124 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3694-5287","authenticated-orcid":false,"given":"Maria","family":"Lui","sequence":"additional","affiliation":[{"name":"IRCCS Centro Neurolesi \u201cBonino-Pulejo\u201d, Via Provinciale Palermo, Contrada Casazza, 98124 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1016\/S1474-4422(21)00030-2","article-title":"Challenges in the diagnosis of Parkinson\u2019s disease","volume":"20","author":"Tolosa","year":"2021","journal-title":"Lancet Neurol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e0022252025","DOI":"10.1523\/JNEUROSCI.0022-25.2025","article-title":"Striatal Dopamine Actions and Movement: Inferences from Parkinson Disease","volume":"45","author":"Albin","year":"2025","journal-title":"J. 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