Year: 2026
Type: preprint
Abstract: Parkinson’s 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 (αSYN). However, the mechanistic relationship between NM accumulation and αSYN pathology remains unclear. Here, we reveal a bidirectional pathogenic relationship between αSYN and NM. In human post-mortem midbrain tissue, ventral nigral neurons with high NM content display increased αSYN 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 αSYN accelerates NM buildup, enhances αSYN oligomerization, and aggravates nigrostriatal degeneration. Mechanistically, αSYN 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 αSYN accelerates NM synthesis through disrupted dopamine compartmentalization, while NM accumulation further promotes αSYN aggregation and neuronal loss. This αSYN-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.
Language: English
Subfield: Clinical Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7223208237