Parkinson’s disease: the affected neurons have finally been identified

Parkinson’s disease is a chronic degenerative neurological disease. The main symptoms include tremor, muscle stiffness and slow movement. The loss of dopamine neurons is a crucial pathological feature of Parkinson’s disease. Current treatments, such as levodopa, make it possible to compensate for the dopamine deficiency and thus relieve the symptoms, but of course do not make it possible to restore the lost neurons. Identifying the most vulnerable nerve cells and understanding the mechanisms that induce their degeneration can pave the way for new therapeutic options.

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A 1st single cell sequencing of dopamine neurons

The laboratory of Evan Macosko, a member of the Broad Institute and a psychiatrist at Massachusetts General Hospital, has a strong interest in brain diseases. He and his team have developed a tool called Slide-seq to locate the expression of all genes in situ, to discover the pathogenic mechanisms of neuropsychiatric diseases. In a new study, recently published in Nature Neuroscience, they dealt with single cell genomic profiling of dopamine neurons; they were thus able to accurately identify the neurons that were specifically affected by Parkinson’s disease.

Dopamine-producing neurons (in green) in the brain tissue of deceased patients with Parkinson’s disease

The researchers developed a protocol to enrich and profile the transcription of dopamine neurons taken from deceased patients with Parkinson’s disease and dementia and from others who died without any cognitive impairment; they tested a total of 387,483 neural nuclei, including 22,048 dopaminergic neuron profiles. While previous studies have suggested that there are two or three types of dopaminergic neurons in the midbrain, the team identified 10 different subtypes of these neurons and identified each of them precisely in the substantia nigra using the Slide-seq tool.

One of these subtypes appeared to be particularly vulnerable to the effects of DNA sequence variations associated with Parkinson’s disease; it was marked by expression of the AGTR1 gene and was spatially confined to the ventral part of the substantia nigra pars compacta – consistent with previously identified patterns of neuronal degeneration in dementia. This group of neurons was largely absent in people with Parkinson’s disease, suggesting that they are the first to degenerate when the disease strikes.

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Parkinson’s: gene expression specific for vulnerable cells

Previous studies had already shown that variations in certain genes and genetic regions were associated with an increased risk of developing the disease. However, the team found that these genes were primarily expressed in dying cells. In other words, these genes should be considered as inherent risk factors (because they act directly in degenerating cells).

The researchers also observed in postmortem tissue that transcription factors associated with cell death processes – such as the p53 gene, located on chromosome 17 – are active in dying cells from patients with Parkinson’s disease, suggesting specific mechanisms of cell death in this pathological context.

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These specific neurons are therefore particularly vulnerable to degeneration in people with a genetic predisposition to the disease. ” Human genetics work in these cells to make them more vulnerable to cell death compared to other related dopamine neuron subtypes, which do not die as much and do not express as many of these risky genes. “Macosko explains in a press release.

It will probably be years before the team’s results benefit patients, but Macosko is optimistic about their potential: This is definitely the most important disease research my lab has done so far. “In the meantime, these findings may help to develop transplantable dopamine neurons that can replace the most vulnerable neurons in patients’ brains. They also highlight the specific cell types and pathways that gene therapy efforts should focus on in the future.

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