Alpha-synuclein and neuromelanin converge to promote Parkinsons disease pathology
- 1Vall d'Hebron Research Institute
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.
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BibTeX
@misc{nicolauvera2026alphasynuclein,
title = {{Alpha-synuclein and neuromelanin converge to promote Parkinsons disease pathology}},
author = {A. Nicolau-Vera and M. Gonzalez-Sepulveda and J. M. Cladera-Sastre and T. Cuadros and A. Parent and G. Roch and J. Marongiu and B. Huynh and A. A. Mahabadian and F. Su and Z. Chatterton and J. Hoyo and A. Laguna and Y. Fu and G. Halliday and M. Vila},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.19.760151},
url = {https://www.biorxiv.org/content/10.64898/2026.10.19.760151v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Alpha-synuclein and neuromelanin converge to promote Parkinsons disease pathology
AU - A. Nicolau-Vera
AU - M. Gonzalez-Sepulveda
AU - J. M. Cladera-Sastre
AU - T. Cuadros
AU - A. Parent
AU - G. Roch
AU - J. Marongiu
AU - B. Huynh
AU - A. A. Mahabadian
AU - F. Su
AU - Z. Chatterton
AU - J. Hoyo
AU - A. Laguna
AU - Y. Fu
AU - G. Halliday
AU - M. Vila
PY - 2026
DA - 2026/10/19
PB - bioRxiv
DO - 10.64898/2026.10.19.760151
UR - https://www.biorxiv.org/content/10.64898/2026.10.19.760151v1
AB - 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.
ER -