Role of Neuromelanin in Parkinson's Disease and Brain Aging

Study Rationale:
In Parkinson's disease (PD), there is a selective degeneration of brain cells that contain the dark-brown pigment neuromelanin, especially dopamine-producing cells in part of the brain called the substantia nigra (which receives its name because of the presence of this dark pigment). In humans, neuromelanin accumulates progressively with age. Increasing age is the main risk factor for developing PD. The physiological significance of neuromelanin and its potential contribution to PD remain unknown because, in contrast to humans, commonly used laboratory models, lack neuromelanin.

Hypothesis:
We hypothesize that the progressive, age-dependent accumulation of neuromelanin interferes with normal cellular function, resulting in dysfunction and eventual cell death when reaching a threshold, culminating in PD.

Study Design:
To assess the potential role of neuromelanin in PD, we generated the first experimental model exhibiting age-dependent production and accumulation of genuine, human-like neuromelanin within PD-vulnerable cells, at levels up to those reached in elderly humans. Using this unique model, we found that progressive neuromelanin accumulation ultimately compromises cell function and triggers the features typical of PD patients, including motor impairment, formation of Lewy bodies and neurodegeneration. In this project we will examine in detail some of the molecular mechanisms underlying the observed effects linked to age-dependent neuromelanin accumulation.

Impact on Diagnosis/Treatment of Parkinson's disease:
By deciphering the molecular mechanisms underlying neuromelanin-linked pathology, our results should lay the groundwork for the development of novel therapeutic strategies aimed at maintaining or decreasing neuromelanin levels below their pathogenic threshold in order to prevent, halt or delay cell dysfunction and degeneration linked to PD.

Next Steps for Development:
Our project may lead to a paradigm shift in the study of PD and, in a broader sense, brain aging. Indeed, strategies to modulate neuromelanin levels may provide unprecedented therapeutic opportunities to prevent, halt or delay cell dysfunction and degeneration linked to both PD and brain aging.