It’s been more than a 100 years since Konstantin Tretiakoff, a doctoral student at the Salpêtrière Hospital in Paris, reported for the first time in his remarkable PhD thesis (1919) the presence of a marked loss of pigmented neurons in the substantia nigra, visible with the naked eye, in the brains of patients with Parkinson’s disease (PD). While this finding failed to gain him any significant recognition during his lifetime, his observation remains to this day the cardinal pathologic diagnostic criterion for PD. The loss of nigral pigmented neurons, which we now know produce the neurotransmitter dopamine, leads to the classical motor features of PD and constitutes the only robust clinico-pathological correlation associated with the disease. The pigment contained within these neurons, termed neuromelanin because of its similar appearance to the cutaneous melanin that colors our skin, is so abundant in the substantia nigra of the healthy human brain that this structure can be seen with the naked eye in autopsied brains as a darkened area (hence the origin of the name given to this particular brain region, literally meaning “black stuff”). Later, other neuromelanin-containing neurons in different brain regions were also found to consistently degenerate in PD, such as noradrenaline-producing neurons of the locus coeruleus, the loss of which is associated with some of the non-motor features of the disease.

In humans, neuromelanin first becomes observable at approximately three years of age and progressively accumulates over time within the cells in which it has been produced, as neurons apparently lack the mechanisms for degrading or eliminating this pigment. As a consequence, neuromelanin progressively builds up with age inside these neurons until occupying most of the neuronal cell body. Importantly, aging is the main risk factor for developing PD, although the molecular substrate linking PD with aging is currently unknown.

Despite the close and long-established association between neuromelanin and PD, the role of neuromelanin in the healthy human brain and its potential contribution to PD remain virtually unknown. This lack of knowledge mostly lies in the fact that, in contrast to humans, laboratory animal species commonly used in experimental research, such as rodents, lack neuromelanin. In fact, the great abundance of neuromelanin in the brainstem is unique to humans, as a macroscopic dark pigmentation of this brain area is not observed in other animal species. Remarkably, humans are also the only species that spontaneously develops PD. Consequently, a factor so intimately linked to PD such as neuromelanin has been surprisingly neglected to date in pre-clinical PD research, as current experimental animal models of the disease, mostly in rodents, lack this brain pigment.

To overcome this major limitation, we recently developed by genetic manipulation the first experimental in vivo rodent model exhibiting age-dependent production and accumulation of human-like neuromelanin within PD-vulnerable nigral neurons, at levels up to those reached in elderly humans. Using this animal model we then found that progressive intracellular build-up of neuromelanin with age ultimately compromised neuronal function when allowed to accumulate above a specific threshold, eventually triggering in these animals age-dependent pathological features of PD, including motor deficits, Lewy pathology and nigrostriatal neurodegeneration. Relevant to humans, we also found that intracellular neuromelanin levels reach this pathogenic threshold in PD patients and subjects with incidental Lewy body disease (i.e. clinically healthy individuals that exhibit Lewy pathology at autopsy and who are considered to represent early, presymptomatic stages of PD). Importantly, the lowering of intracellular neuromelanin to levels below this pathogenic threshold, by promoting with gene therapy the release of neuromelanin outside of the neurons, diminished Lewy pathology, attenuated nigro-striatal neurodegeneration and reversed hypokinesia in our neuromelanin-producing rodents.

These results indicate that an excessive production/accumulation of neuromelanin within neurons can compromise neuronal function and trigger PD pathology. Because all humans normally accumulate neuromelanin with age, our results imply that all humans could potentially develop PD if they were to live long enough to reach the pathogenic threshold of intracellular neuromelanin accumulation. Supporting this concept, the proportion of apparently healthy elderly subjects exhibiting Lewy pathology, age-dependent degeneration/dysfunction of pigmented neurons or PD-like motor dysfunction greatly exceeds that of PD. In PD patients, the disease could be triggered either by an accelerated or abnormally increased production of neuromelanin, thus reaching earlier the pathogenic threshold of intracellular neuromelanin accumulation, or by the occurrence of concomitant PD-related pathogenic factors (such as PD-linked genetic mutations or exposure to environmental toxins) that may lower the pathogenic threshold of neuromelanin accumulation. In any event, based on our results, the development of strategies able to modulate intracellular neuromelanin levels may provide unprecedented therapeutic opportunities to prevent, halt or delay neuronal dysfunction and degeneration linked to PD and brain aging.

Overall, the introduction into experimental in vivo research of a factor so intimately linked to PD such as neuromelanin, which has been so-far neglected in PD animal modeling, may lead to a paradigm shift in the study of PD, open up new research avenues and, ultimately, have important near-future implications for the therapeutic management of PD and, in a broader sense, brain aging.

Articles:
- Brain tyrosinase overexpression implicates age-dependent neuromelanin production in Parkinson’s disease pathogenesis
- Neuromelanin, aging, and neuronal vulnerability in Parkinson's disease
- Intracellular crowding by age-dependent neuromelanin accumulation disrupts neuronal proteostasis and triggers Parkinson disease pathology

This blog was selected for a WPC Research Spotlight. The authors were interviewed about their work in January 2021.

You may view the interview here:

Miquel Vila, MD, PhD is a Professor at the Catalan Institution for Research and Advanced Studies (ICREA) and leads the Neurodegenerative Diseases Research Group at the Vall d’Hebron Research Institute in Barcelona. He has been involved in many past World Parkinson Congresses and is currently the Co-chair of the Local Organizing Committee for the 6th World Parkinson Congress to be held in Barcelona, Spain from 7-10 June 2022.

Ideas and opinions expressed in this post reflect that of the author(s) solely. They do not necessarily reflect the opinions or positions of the World Parkinson Coalition®