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Nat Neurosci DOI:10.1038/s41593-022-01061-1

Single-cell genomic profiling of human dopamine neurons identifies a population that selectively degenerates in Parkinson's disease.

Publication TypeJournal Article
Year of Publication2022
AuthorsKamath, T, Abdulraouf, A, Burris, SJ, Langlieb, J, Gazestani, V, Nadaf, NM, Balderrama, K, Vanderburg, C, Macosko, EZ
JournalNat Neurosci
Date Published2022 May
KeywordsDopaminergic Neurons, Genomics, Humans, Parkinson Disease, Substantia Nigra

The loss of dopamine (DA) neurons within the substantia nigra pars compacta (SNpc) is a defining pathological hallmark of Parkinson's disease (PD). Nevertheless, the molecular features associated with DA neuron vulnerability have not yet been fully identified. Here, we developed a protocol to enrich and transcriptionally profile DA neurons from patients with PD and matched controls, sampling a total of 387,483 nuclei, including 22,048 DA neuron profiles. We identified ten populations and spatially localized each within the SNpc using Slide-seq. A single subtype, marked by the expression of the gene AGTR1 and spatially confined to the ventral tier of SNpc, was highly susceptible to loss in PD and showed the strongest upregulation of targets of TP53 and NR2F2, nominating molecular processes associated with degeneration. This same vulnerable population was specifically enriched for the heritable risk associated with PD, highlighting the importance of cell-intrinsic processes in determining the differential vulnerability of DA neurons to PD-associated degeneration.


Alternate JournalNat Neurosci
PubMed ID35513515
PubMed Central IDPMC9076534
Grant ListF30 AG069446 / AG / NIA NIH HHS / United States
U01MH124602 / / U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH) /
U01 MH124602 / MH / NIMH NIH HHS / United States
DP2 AG058488 / AG / NIA NIH HHS / United States
DP2AG058488 / / U.S. Department of Health & Human Services | National Institutes of Health (NIH) /
F30AG069446-01 / / U.S. Department of Health & Human Services | National Institutes of Health (NIH) /