Neuromelanin, aging, and neuronal vulnerability in Parkinson's disease.

Miquel Vila

doi:10.1002/mds.27776

Abstract

Neuromelanin, a dark brown intracellular pigment, has long been associated with Parkinson's disease (PD). In PD, neuromelanin‐containing neurons preferentially degenerate, tell‐tale neuropathological inclusions form in close association with this pigment, and neuroinflammation is restricted to neuromelanin‐containing areas. In humans, neuromelanin accumulates with age, which in turn is the main risk factor for PD. The potential contribution of neuromelanin to PD pathogenesis remains unknown because, in contrast to humans, common laboratory animals lack neuromelanin. The recent introduction of a rodent model exhibiting an age‐dependent production of human‐like neuromelanin has allowed, for the first time, for the consequences of progressive neuromelanin accumulation—up to levels reached in elderly human brains—to be assessed in vivo. In these animals, intracellular neuromelanin accumulation above a specific threshold compromises neuronal function and triggers a PD‐like pathology. As neuromelanin levels reach this threshold in PD patients and presymptomatic PD patients, the modulation of neuromelanin accumulation could provide a therapeutic benefit for PD patients and delay brain aging. © 2019 The Author. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Highlights

Supporting a pathogenic role for intracellular neuromelanin accumulation when allowed to accumulate above a specific threshold within individual neurons, the lowering of intracellular neuromelanin to levels below this pathogenic threshold in human tyrosinase (hTyr)-overexpressing rodents, in part by promoting the release of intracellular neuromelanin to the outside of the cell, diminished Parkinson’s disease (PD)-linked inclusion formation, attenuated nigrostriatal neurodegeneration, and reversed hypokinesia in these animals.[43]. These results demonstrate the feasibility and therapeutic potential of modulating intracellular neuromelanin levels in vivo and indicate that strategies to maintain or decrease intracellular neuromelanin to levels below its pathogenic threshold may provide unprecedented therapeutic opportunities to prevent, halt, or delay neuronal dysfunction and degeneration linked to PD and brain aging (Fig. 2)
The development of the first rodent model producing human-like neuromelanin in PD-vulnerable dopaminergic nigral neurons has allowed for the first time to experimentally assess the consequences of age-dependent neuromelanin accumulation up to levels reached in elderly humans in an in vivo setting. The observation in this animal model that age-dependent intracellular neuromelanin buildup leads to PD-like neuronal dysfunction and neurodegeneration when reaching a certain pathogenic threshold of accumulation may have far-reaching implications for both PD and brain aging
Understanding these mechanisms may help unravel why PD patients would reach the pathogenic threshold of neuromelanin accumulation earlier than healthy subjects

Summary

SCIENTIFIC PERSPECTIVE

A century ago, in 1919, Konstantin Tretiakoff reported for the first time in his remarkable doctorate thesis the presence of a marked loss of pigmented neurons in the substantia nigra (SN), visible with the naked eye, in the brains of Parkinson’s disease (PD) patients.[1]. Modeling Neuromelanin Production In Vivo: Age-Dependent Intracellular Neuromelanin Accumulation Drives

PD Pathology

Findings

Concluding Remarks and Future Directions