{
  "abstract": "Parkinsons disease (PD) is defined by the preferential degeneration of neuromelanin (NM)-containing dopamine-producing neurons in the substantia nigra (SN), accompanied by intraneuronal inclusions rich in alpha-synuclein (aSYN). However, the mechanistic relationship between NM accumulation and aSYN pathology remains unclear. Here, we reveal a bidirectional pathogenic relationship between aSYN and NM. In human post-mortem midbrain tissue, ventral nigral neurons with high NM content display increased aSYN mRNA expression and are preferentially lost in PD. In a rat model that recapitulates age-dependent, human-like NM accumulation via targeted tyrosinase (TYR) expression, co-expression of aSYN accelerates NM buildup, enhances aSYN oligomerization, and aggravates nigrostriatal degeneration. Mechanistically, aSYN oligomerization in NM-producing rats decreases vesicular dopamine storage and impairs vesicle fusion with the plasma membrane, increasing cytosolic dopamine availability for oxidation into NM. Together, these findings support a pathogenic feedback loop in which elevated aSYN accelerates NM synthesis through disrupted dopamine compartmentalization, while NM accumulation further promotes aSYN aggregation and neuronal loss. This aSYN-NM axis may underlie the preferential vulnerability of pigmented nigral neurons in PD and provide a mechanistic framework for the development of future targeted therapeutics.",
  "abstract_shown": true,
  "affiliations": [
    "Vall d'Hebron Research Institute"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 16,
  "authors": [
    {
      "name": "A. Nicolau-Vera"
    },
    {
      "name": "M. Gonzalez-Sepulveda"
    },
    {
      "name": "J. M. Cladera-Sastre"
    },
    {
      "name": "T. Cuadros"
    },
    {
      "name": "A. Parent"
    },
    {
      "name": "G. Roch"
    },
    {
      "name": "J. Marongiu"
    },
    {
      "name": "B. Huynh"
    },
    {
      "name": "A. A. Mahabadian"
    },
    {
      "name": "F. Su"
    },
    {
      "name": "Z. Chatterton"
    },
    {
      "name": "J. Hoyo"
    },
    {
      "name": "A. Laguna"
    },
    {
      "name": "Y. Fu"
    },
    {
      "name": "G. Halliday"
    },
    {
      "affs": [
        0
      ],
      "name": "M. Vila"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/c1361q8v7gskd.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.10.19.760151",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.10.19.760151v1.full",
  "id": "c1361q8v7gskd",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.10.19.760151v1",
  "language": null,
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "biorxiv",
      "neuroscience"
    ],
    [
      "openalex",
      "2728|Parkinson's Disease Mechanisms and Treatments"
    ]
  ],
  "openalex": "W7223208237",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.10.19.760151v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-19",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/c1361q8v7gskd.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:29:27Z",
      "native_id": "10.64898/2026.10.19.760151",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.10.19.760151v1"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "biorxiv:neuroscience",
      "subfield": "neuroscience"
    }
  ],
  "title": "Alpha-synuclein and neuromelanin converge to promote Parkinsons disease pathology",
  "title_text": "Alpha-synuclein and neuromelanin converge to promote Parkinsons disease pathology",
  "type": "preprint",
  "updated_at": "2026-10-30T12:29:27Z",
  "url": "https://research.draconitic.com/paper/c1361q8v7gskd",
  "venue": "bioRxiv",
  "versions": []
}