Neuromelanin: a new angle on Parkinson’s

Original article: Brain tyrosinase overexpression implicates age-dependent neuromelanin production in Parkinson’s disease pathogenesis. Nature Communications: March 9, 2019. 

The takeaway

A recent animal study on neuromelanin has suggested that it could be a key player in the loss of striatal dopaminergic neurons mediating movement in Parkinson’s. It may interfere with waste clearance in these neurons.

Why is it important?

While these findings do not account for the fate of neurons in the rest of the brain, they suggest an interesting angle on a substance which was previously thought to be neuroprotective. These results also indicate a potentially useful new animal for Parkinson’s disease.

Impact opinion

“One of the major limiting factors of research into disease modifying therapies for Parkinson’s is the lack of proper models of the condtion. Previously crude neurotoxin models have been used which have little disease relevance. This new report is very exciting as it may not only provide us with a useful new model of Parkinson’s, but it could also be providing us with some key insights into the nature of the biology underlying the condition. It will be important to see independent replication of the results before we get too excited though.”

Background

Neuromelanin (melanin = dark substance in Greek) is found in a very small number of neurons in the brain. This is what gives the substantia nigra (literally dark substance in Latin), a key movement related centre in the brain that degenerate in Parkinson’s, its colour, which can actually be seen with the naked eye. It is also found in other much smaller regions, such as the locus coeruleus (meaning blue area in Latin) which also degenerates in Parkinson’s and regulates sleep, among other functions.

Previously, neuromelanin was believed to be neuroprotective, as it mops up nasty toxins (such as free radicals and excess iron and copper). It increases in humans with age, but it is absent in mice and rats. The researchers who conducted this study asked whether neuromelanin may actually be triggering neuronal death, rather than protecting cells, once it accumulates to a high enough level with ageing.

The details

To answer this broader question, they first caused rats to produce neuromelanin in the substantia nigra. They did this by inserting the genetic instructions for a particular enzyme called tyrosinase into a virus, which had been rendered otherwise safe for the animals. They then injected this virus into the substantia nigra dopamine neurons of the experimental animals. They found that at 1-2 months, these neurons appeared dark due to neuromelanin levels similar to those seen in neurons taken from the brains of healthy 80 yr individuals, and at 2-4 months, as neuromelanin continued to build up, this was similar to the levels seen in the brains of people who had had Parkinson’s. Around this time, the mice also began to show problems with movement as dopamine neurons began to die.

The researchers also observed that as these dopamine neurons died and released neuromelanin into their surrounding space, microglia which are the resident immune cells in the brain, became activated. In addition, they observed Lewy bodies, which are dense clumps of alpha-synuclein, and other markers indicating that the waste disposal systems inside cells responsible for autophagy may be disrupted. To check if this was the case, they injected directly into the substantia nigra a substance called TFEB which is a master regulator of autophagy. They observed that neuromelanin was reduced, as were Lewy bodies. This is also improved some of the movement problems seen in these animals.

Next steps

An important next step will be to better characterize this new animal model for Parkinson’s, in order to better understand how it compares to what we know occurs in the human brain. Eventually, if deemed suitable, potential new candidate therapies could be tested in this model first.

Original article: Carballo-Carbajal, I., Laguna, A., Romero-Gimenez, J., Cuadros, T., Bove, J., Martinez-Vicente, M., . . . Vila, M. Brain tyrosinase overexpression implicates age-dependent neuromelanin production in Parkinson’s disease pathogenesis. Nature Communications: March 9, 2019. 

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