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Hypoxia\u2013ischemia following blood flow disturbance would recruit and activate leukocytes and induce the infiltration of peripheral immune cells into neural tissue. The excess of toxic factors produced by hyperactive immune cells, such as myeloperoxidase and its derivatives, would cause the oxidation of lipids, proteins, and biogenic monoamines such as dopamine, which in turn would facilitate the accumulation and precipitation of neuromelanin, lipofuscin, and alpha-synuclein. In addition, neuromelanin and lipofuscin precipitates may accentuate the misfolding and aggregation of alpha-synuclein. This \u201camplification\u201d mechanism could help explain the crucial role of pigmented neurons in the onset of Parkinson\u2019s disease pathology, triggering abnormal neurotoxic alpha-synuclein spread throughout the nervous system from the \u201ccritical point\u201d of origin, and enabling a self-perpetuating degenerative process. The proposed hypothesis may have implications for the identification of new therapeutic targets, early prevention strategies, and the development of vascular and\/or immune biomarkers.<\/jats:p>","DOI":"10.3390\/antiox15020201","type":"journal-article","created":{"date-parts":[[2026,2,3]],"date-time":"2026-02-03T10:03:29Z","timestamp":1770113009000},"page":"201","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Pathophysiological Model of Parkinson\u2019s Disease Based on Microvascular Flow Disturbance and Leukocyte-Mediated Oxidative Injury in Critical Pigmented Neuronal Niches"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0724-6049","authenticated-orcid":false,"given":"Emilio","family":"Fern\u00e1ndez-Espejo","sequence":"first","affiliation":[{"name":"Royal College of Physicians of Seville, 41013 Seville, Spain"},{"name":"Unidad Cl\u00ednica de Neurolog\u00eda, Instituto de Investigaci\u00f3n Biom\u00e9dica de M\u00e1laga & Plataforma en Nanomedicina-IBIMA Plataforma BIONAND, Hospital Regional Universitario, 29590 M\u00e1laga, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4516-5795","authenticated-orcid":false,"given":"Fernando","family":"Rodr\u00edguez de Fonseca","sequence":"additional","affiliation":[{"name":"Unidad Cl\u00ednica de Neurolog\u00eda, Instituto de Investigaci\u00f3n Biom\u00e9dica de M\u00e1laga & Plataforma en Nanomedicina-IBIMA Plataforma BIONAND, Hospital Regional Universitario, 29590 M\u00e1laga, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,3]]},"reference":[{"key":"ref_1","first-page":"S281","article-title":"Brain-First versus Gut-First Parkinson\u2019s Disease: A Hypothesis","volume":"9","author":"Borghammer","year":"2019","journal-title":"J. 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