Specific brain circuits that are highly melanized (build-up of the dark pigment neuromelanin) with age are primarily affected, particularly early, in Parkinson's disease. Models incorporating this aspect of Parkinson's disease have only been developed recently and show that increased neuromelanin production causes neurodegenerative changes consistent with Parkinson's disease. The regulators of cellular neuromelanin metabolism have not been determined, the effect of neuromelanin on normal activity in these pathways has not been defined, the potential for neuromelanin aggregates to increase alpha-synuclein accumulation has not been evaluated, and the impact of extracellular neuromelanin on detrimental inflammatory processes has not been assessed.
Activity in melanized brain circuits is a dominant factor in the initiation of Parkinson’s disease and sustains its progression by seeding pathology in connected regions and providing the stimulus for chronic inflammation. Manipulating neuromelanin production and/or brain circuit activity can ameliorate these deficits.
Parallel experiments will be performed in mice and non-human primates in which neuromelanin production has been induced for comparison with neuromelanin-producing neurons in people with prodromal and early Parkinson’s disease. To test whether activity in melanized brain circuits is a dominant factor in the initiation of Parkinson’s disease, spatiotemporal activity mapping, imaging and other techniques will be used, and manipulating neuromelanin production and/or brain circuit activity will be assessed as potential treatments. To determine if neurons spread Parkinson’s disease pathology through their connectivity, seeding experiments will be performed and impacts on behaviour and neurodegeneration assessed. To determine how non-neuronal mechanisms are involved in disease progression, high-resolution microscopy and cell-specific details of changes in extracellular spaces and infiltration of non-neuronal cells into the brain will be assessed.
Impact on Diagnosis/Treatment of Parkinson’s Disease:
Diagnosis of neuromelanin changes in the brain are already being assessed for their diagnostic potential, but this study will determine their focus and rate of change with respect to neural activity and clinical features. We will also identify if reducing neuromelanin levels stabilizes pathology and restores brain activity.
Next Steps for Development:
For diagnosis, validation of the assessment of the change in neuromelanin-signal in the pons (part of the brainstem) with respect to the midbrain will be evaluated. For treatment, reducing neuromelanin using the combination of techniques utilized successfully in the non-human primates should be tested in patients at the onset of Parkinson’s disease.