Scientists probing the biological underpinnings of Parkinson's disease have made an important discovery, shedding new light on the demise of cells that drives neurodegeneration linked to the condition. The breakthrough helps explain why some neurons are susceptible to this form of cell death, and raises some new possibilities around how it might be prevented.
One of the hallmarks of Parkinson's disease is the death of neurons that generate the neurotransmitter dopamine. With a decline in dopamine comes a deterioration in motor skills and other symptoms of the condition, so devising ways to shore up its supply is a key priority for scientists in the field.
This could come from existing drugs such as levodopa, which makes its way to the brain and is converted into dopamine, or electrical stimulation, an established treatment technique that is improving all the time. Because the loss of neurons is irreversible, however, we are also seeing scientists focus on techniques that replace them with versions grown from stem cells, with some therapies recently making it to human trials.
Scientists at the Broad Institute of MIT and Harvard are approaching this problem by attempting to better understand what causes the neurons to die in the first place. The dopamine-producing neurons lost through Parkinson's reside deep in the midbrain within a structure called the substantia nigra, and scientists have been unable to understand the molecular features that makes them in particular prone to death.
The team's new research involved analyzing postmortem brain samples from Parkinson's patients along with healthy subjects, and comparing single-cell gene expressions between them. This enabled them to identify the different dopamine neurons in the human midbrain, and while previous research had suggested there to be two or three types, the scientists identified 10 altogether. Among that family of 10, the scientists identified one cell type they describe as especially vulnerable, identified by certain transcription factors and expression of a gene called AGTR1.
"Our results help explain a longstanding mystery about Parkinson's: why this particular subset of dopamine cells dies in the midbrain," said Macosko. "These dying cells express more risk-related variants compared to other cell types and to similar cells from people without Parkinson's. Hence human genetics is acting within these cells to make them more vulnerable to cell death, as compared to other related dopamine neurons subtypes, which don't die as much and don't express as many of these risk genes."
This points to specific mechanisms that cause cell death in Parkinson's, and together these vulnerabilities constitute a kind of gene expression signature for at-risk neurons. This in turn lays a foundation for ongoing efforts to engineer dopamine-producing neurons in the lab. Researchers have already demonstrated an ability to grow these from stem cells, and even demonstrated how they might restore broken circuits in the midbrain and improve motor symptoms.
"There are many efforts underway now to engineer dopamine neurons in a dish to transplant into patients with Parkinson's disease," said Macosko. "What we report here is the actual gene expression signature of the vulnerable neurons. This information will help these groups in their efforts."
Further, as these mechanisms had been seen in mouse studies but not in human cells before, the research also demonstrates a way of visualizing disease signatures in neurons in post-mortem brain samples. This raises the prospect of not just transplantation of cells engineered to produce dopamine, but alternative therapies that target the signaling pathways causing cell death.
"There are already some experimental neuron-targeting gene therapy trials in Parkinson's disease, and this study highlights specific cell types and pathways that those gene therapy efforts should focus on," said Macosko.
The research was published in the journal Nature.
Source: Broad Institute
