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Neuromelanin accumulation drives endogenous synucleinopathy in non-human primates
Julia Chocarro1,2,3, Alberto J Rico1,2,3, Goiaz Ariznabarreta1,2,3
1CNS Gene Therapy Program, Center for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain.
Brain : a Journal of Neurology
|September 28, 2023
Summary
Neuromelanin accumulation in macaques triggered Parkinson's disease (PD) pathology, including alpha-synuclein aggregation and neuron loss. This finding suggests targeting neuromelanin could be a novel therapeutic strategy for PD.
Area of Science:
- Neuroscience
- Pathology
- Animal Models
Background:
- Neuromelanin, a pigment in substantia nigra dopaminergic neurons, is implicated in Parkinson's disease (PD) pathogenesis.
- A lack of neuromelanin in common lab animals has limited PD research models.
Purpose of the Study:
- To develop a novel macaque model of PD that accurately replicates human neuropathology.
- To investigate the role of neuromelanin accumulation in triggering PD-like pathology.
Main Methods:
- Adeno-associated viral vectors encoding the human tyrosinase gene were used to induce neuromelanin accumulation in macaque substantia nigra.
- Neuropathological changes, including alpha-synuclein aggregation and dopaminergic neuron degeneration, were analyzed.
Main Results:
- Neuromelanin accumulation in macaques mimicked human levels and induced endogenous alpha-synucleinopathy.
- Progressive degeneration of dopaminergic neurons and Lewy body-like inclusions in cortical areas were observed.
- Evidence suggests neuromelanin triggers alpha-synuclein aggregation, supporting trans-synaptic spread.
Conclusions:
- A new macaque model accurately reflects PD neuropathology.
- Neuromelanin accumulation is a key factor in initiating PD-related alpha-synuclein aggregation.
- Reducing neuromelanin levels presents a potential therapeutic avenue for Parkinson's disease.
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