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Hence, our aim was to explore whether central and peripheral proVGF changes occur during early dopaminergic dysfunction. To investigate this, we employed a rat model mimicking early-stage PD by injecting the SN unilaterally with an adeno-associated virus (AAV) carrying either the human \u03b1-synuclein (\u03b1-syn;\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200919) or green fluorescent protein (GFP;\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200918) gene. After conducting motor assessments and sacrificing the animals, brain and blood samples were collected. Tyrosine hydroxylase (TH)-, glutamic acid decarboxylase (GAD)-, and phosphorylated (p)-\u03b1-syn antibodies were used for immunohistochemistry (IHC), while an antibody targeting the C-terminus of proVGF was employed for IHC, western blot (WB), and enzyme linked immunosorbent asssay (ELISA). The \u03b1-syn overexpression caused a modest (~\u200930%) reduction in TH immunoreactivity within the SN\u2014without affecting the striatum\u2014and did so without producing overt motor symptoms, effectively modeling a pre-symptomatic PD stage. This early dopaminergic dysfunction was accompanied by decreased immunostaining for both proVGF C-trerminus and GAD in the SN, but not the striatum. Reduction in plasma proVGF levels were also observed, indicating systemic changes during initial dopaminergic impairment. Analysis using WB confirmed a decrease in a 70\u00a0kDa band consistent with proVGF in both SN and plasma. These findings suggest proVGF as a promising early biomarker for PD, opening new avenues for intervention before the onset of clinical symptoms.\n                  <\/jats:p>","DOI":"10.1007\/s11064-025-04586-6","type":"journal-article","created":{"date-parts":[[2025,10,30]],"date-time":"2025-10-30T10:19:43Z","timestamp":1761819583000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Early Dopaminergic Dysfunction Induces PRO-VGF Changes in Blood and Brain of Rats with Alpha-Synuclein Overexpression"],"prefix":"10.1007","volume":"50","author":[{"given":"Elias","family":"Manca","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sara","family":"Corsi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Silvia","family":"Fanni","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Barbara","family":"Noli","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Antonio Luigi","family":"Manai","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giuseppina","family":"Bassu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Corda","family":"Giulia","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria Antonietta","family":"Casu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Roberto","family":"Frau","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pardon","family":"Marie-Christine","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Graziella","family":"Cappelletti","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Samanta","family":"Mazzetti","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Manolo","family":"Carta","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cristina","family":"Cocco","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,10,30]]},"reference":[{"key":"4586_CR1","doi-asserted-by":"publisher","first-page":"839","DOI":"10.1038\/42166","volume":"388","author":"MG Spillantini","year":"1997","unstructured":"Spillantini MG, Schmidt ML, Lee VM-Y et al (1997) \u03b1-Synuclein in lewy bodies. 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