Evan Macosko, an institute member at the Stanley Center for Psychiatric Research at the Massachusetts General Hospital, and a graduate student Tushar Kamath, an academic associate, and colleagues conducted a comprehensive molecular analysis of the dopamine-producing neurons lost in Parkinson''s disease. By examining single-cell gene expression patterns in postmortem brain samples from patients with Parkinson''s disease and people never diagnosed with the condition, they identified ten distinct subtypes of dopamine neurons in the substant
We discussed with Macosko about his team''s findings, which were published in the journal Nature Neuroscience, as well as their implications on patient health. While it will be years before the team''s findings may benefit patients, Macosko is optimistic about their potential: "This is certainly the most significant disease research I''ve ever done so far."
What are the results of this study?
We measured all of the different kinds of dopamine neurons in the human midbrain using a single-nucleus RNA sequencing. These neurons are particularly beneficial to Parkinson''s and schizophrenia, especially because all antipsychotic drugs modify dopamine signaling. Several studies also demonstrated that there were two or three kinds of dopamine neurons in the midbrain, among which one was particularly susceptible to cell death in Parkinson''s disease. Finally, using Slide-seq, a technology my lab has been working with
Variation in certain genes and genetic regions can increase a person''s risk of developing Parkinson''s disease, according to previous studies. This suggests that these risk genes are preferentially expressed in the cells that die, indicating that they are considered intrinsic risk factors. This suggests that these risk genes largely act within the cells that die, while in accordance with Alzheimer''s disease, because they act not in neurons but in a particular type of cell in the brain microglia, which, through some neuroimmune mechanism, results in
The most commonly identified transcription factors in cell death processes, such as p53, are active in Parkinson''s patients dying cells, suggesting specific mechanisms for how cells died in Parkinson''s disease.
What do you think of these findings? What do they teach us about Parkinson''s disease?
Because this particular subset of dopamine cells dies in the midbrain, this particular subset of dementia cells express more risk-related mutations than other cell types and similar cells from people without Parkinson''s. Hence human genetics is working within these cells to increase cell death, as compared to other related dopamine neurons subtypes, which do not die as much and do not express as many of these risk genes.
There are also several actions underway to develop dopamine neurons in a dish to transplant into patients with Parkinson''s disease. What we reveal here is the actual gene expression signature of the vulnerable neurons. This information will assist these individuals in their efforts.
Is this a completely new conclusion?
This is the first time anyone has done single-nucleus sequencing comparing human dopamine neurons from patients with Parkinson''s disease with those from healthy controls. So these insights that follow these findings about how genetic risk variants act within these dying neurons are completely new. This is the first time that cell death pathways like p53 have been observed in patients.
Is it possible to hear from some of your conclusions?
We were surprised that only one specific subtype of dopamine neuron was so much vulnerable. Despite previous observations, many populations would be equally vulnerable, although this was not the case. We were also surprised that we could see a p53 activation signature in these neurons. These are postmortem tissue specimens, and the tissue had significantly degraded. But the signature was there.
What significance is this study to understanding Parkinson''s disease biology and for patients?
This is a substantial step for our lab and the field. It demonstrates that we can visualize disease signatures in neurons from postmortem human brains, and that these signatures may guide us to interpretable, actionable hypotheses about Parkinson''s disease.
It underscores the importance of focusing on signaling processes within the neurons that die. 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. This also provides a framework for cell transplantation studies to assist researchers in developing neurons that can replace vulnerable cells.