{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,26]],"date-time":"2025-12-26T04:39:01Z","timestamp":1766723941611,"version":"3.48.0"},"reference-count":35,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2025,12,22]],"date-time":"2025-12-22T00:00:00Z","timestamp":1766361600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Recent studies have identified phosphorylated \u03b1-synuclein in the skin of individuals with neurodegenerative disease. The levels of this protein in the skin have been correlated with disease severity. This protein has been specifically studied in alpha-synucleinopathies such as Parkinsons\u2019 Disease (PD) and Multiple System Atrophy (MSA). Given that skin biopsy studies have often shown high levels of phosphorylated \u03b1-synuclein in the neck area, and that other clinical studies have described easily identifiable changes in facial skin features, this systematic review explores whether age spots, which are very common in sun-exposed areas (hands and face), could serve as early indicators of neurodegenerative disease. We performed a systematic review of the literature in three databases (Google, Scopus and Pubmed) following PRISMA guidelines. We used the following keywords: \u201calpha-synuclein and skin\u201d, \u201calpha-synuclein and skin spots\u201d, \u201calpha-synuclein and solar lentigo\u201d, \u201calpha-synuclein and age spots\u201d, \u201calpha-synuclein and melanocytes\u201d, \u201cskin biopsy and synucleinopathies\u201d, \u201cskin biopsy and neurodegenerative disease\u201d, and \u201cParkinson\u2019s Disease. Eleven studies were identified and included. Based on the study results and preliminary evidence in the literature evaluating the effect of \u03b1-synuclein on keratinocytes and melanocytes, we propose that the accumulation of this protein within the skin may produce visible alterations that can be quantified to enable early, noninvasive detection of neurodegenerative disease.<\/jats:p>","DOI":"10.3390\/ijms27010096","type":"journal-article","created":{"date-parts":[[2025,12,26]],"date-time":"2025-12-26T03:06:02Z","timestamp":1766718362000},"page":"96","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Cutaneous \u03b1-Synuclein and Age Spots in Neurodegeneration: A Systematic Review and Testable Hypothesis"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5510-3814","authenticated-orcid":false,"given":"Arianna","family":"Di Stadio","sequence":"first","affiliation":[{"name":"Life and Health Science Department, Link University, 00165 Rome, Italy"},{"name":"IRCCS Santa Lucia, Laboratory of Neuromotor Physiology, IRCCS Santa Lucia Foundation, 00179 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6505-1680","authenticated-orcid":false,"given":"Pietro","family":"De Luca","sequence":"additional","affiliation":[{"name":"IRCCS Santa Lucia, Laboratory of Neuromotor Physiology, IRCCS Santa Lucia Foundation, 00179 Rome, Italy"},{"name":"Otolaryngology Department Santa Rosa Hospital, 01100 Viterbo, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Beatrice","family":"Francavilla","sequence":"additional","affiliation":[{"name":"Otolaryngology Department, University of Rome Tor Vergata, 00133 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Massimo","family":"Ralli","sequence":"additional","affiliation":[{"name":"UNICAMILLUS, International Medical University, 00131 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stefano","family":"Di Girolamo","sequence":"additional","affiliation":[{"name":"Otolaryngology Department, University of Rome Tor Vergata, 00133 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1183-0013","authenticated-orcid":false,"given":"Iole","family":"Indovina","sequence":"additional","affiliation":[{"name":"IRCCS Santa Lucia, Laboratory of Neuromotor Physiology, IRCCS Santa Lucia Foundation, 00179 Rome, Italy"},{"name":"Department of Systems Medicine and Centre for Space BioMedicine, University of Rome Tor Vergata, 00133 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8363-0195","authenticated-orcid":false,"given":"Giulia","family":"Ciccarese","sequence":"additional","affiliation":[{"name":"Dermatology Department, University of Foggia, 71122 Foggia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laura","family":"Dipietro","sequence":"additional","affiliation":[{"name":"Highland Instruments, Inc., Cambridge, MA 02238, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Klostermeier, S., Li, A., Hou, H.X., Green, U., and Lennerz, J.K. 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