The most vulnerable dopamine neuron subtype

The research record

This is the project's file for this landmark, as written and checked. Sources are listed at the end; anything not yet confirmed is marked "Not yet verified".

Who

Tushar Kamath (first author), Abdulraouf Abdulraouf, Evan Macosko (Broad Institute, senior author) and colleagues. Funding: NIH (grants F30AG069446 to Kamath, DP2AG058488 and U01MH124602 to Macosko) and the Chan Zuckerberg Initiative.

What happened

Dopamine neurons are a tiny fraction of midbrain cells, so the team enriched them from postmortem tissue before sequencing individual nuclei. Across all samples they profiled about 387,000 nuclei, including roughly 22,000 dopamine neurons, and defined ten dopamine-neuron types, mapped to places in the nigra. The paper used 8 control donors and 10 people with Parkinson's or Lewy body dementia. The SOX6+ AGTR1+ type, found in the ventral tier of the nigra, was the most depleted in disease, and the one whose genes were most enriched for Parkinson's genetic risk (landmark 19); stress pathways involving TP53 and NR2F2 were active in it. Nature Neuroscience 25(5):588–595, online 5 May 2022. Three commentaries appeared (Nat Neurosci, Nat Rev Neurol, Mov Disord); no correction or retraction is recorded.

Why it moved us toward a cure

It turns "selective vulnerability" (landmark 93, landmark 57) from a vague idea into a specific, named cell population with a molecular profile. That suggests cell-intrinsic causes, and could help stem-cell groups aim to make the right replacement neurons (landmark 10, landmark 17) and test disease models in the vulnerable type.

The 1991 finding that the ventrolateral tier of the nigra is lost first (landmark 267) set up this question.

Calbindin-rich dopamine neurons had long been known to be spared (landmark 343).

Outcome

Open. Alzforum's commentators raised caveats: few donors (only 8 controls, 6 of them female, with an age range that does not match the cases well), subtypes that blend into each other, uncertain links of some risk genes, the missing resilient ventral tegmental neurons, and the point that RNA from dying cells cannot prove cause. Disease donors also included Lewy body dementia. A drug aimed at this subtype does not yet exist as far as I verified.

Sources

• Kamath et al., Nat Neurosci 2022;25:588–595, DOI 10.1038/s41593-022-01061-1, PMID 35513515 (Broad record)
• Alzforum, "Single-Cell Sleuthing Nabs Neurons Prone to Perish in Parkinson's"
• Donor numbers, enrichment and funding read in the open full text, PMC9076534.
• Not yet verified: independent replication of the AGTR1 finding; any therapy developed from it.