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A molecular census of midbrain dopaminergic neurons in Parkinson’s disease

View ORCID ProfileTushar Kamath, View ORCID ProfileAbdulraouf Abdulraouf, SJ Burris, Vahid Gazestani, View ORCID ProfileNaeem Nadaf, View ORCID ProfileCharles Vanderburg, View ORCID ProfileEvan Z Macosko
doi: https://doi.org/10.1101/2021.06.16.448661
Tushar Kamath
1Broad Institute of Harvard and MIT, Stanley Center for Psychiatric Research, 75 Ames Street. Cambridge, MA, USA
2Harvard Graduate Program in Biophysics, Harvard University
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Abdulraouf Abdulraouf
1Broad Institute of Harvard and MIT, Stanley Center for Psychiatric Research, 75 Ames Street. Cambridge, MA, USA
3Tri-Institutional MD–PhD Program, Weill Cornell Medical College, Rockefeller University and Memorial Sloan Kettering Cancer Center, New York, NY, USA
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SJ Burris
1Broad Institute of Harvard and MIT, Stanley Center for Psychiatric Research, 75 Ames Street. Cambridge, MA, USA
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Vahid Gazestani
1Broad Institute of Harvard and MIT, Stanley Center for Psychiatric Research, 75 Ames Street. Cambridge, MA, USA
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Naeem Nadaf
1Broad Institute of Harvard and MIT, Stanley Center for Psychiatric Research, 75 Ames Street. Cambridge, MA, USA
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Charles Vanderburg
1Broad Institute of Harvard and MIT, Stanley Center for Psychiatric Research, 75 Ames Street. Cambridge, MA, USA
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Evan Z Macosko
1Broad Institute of Harvard and MIT, Stanley Center for Psychiatric Research, 75 Ames Street. Cambridge, MA, USA
4Massachusetts General Hospital, Department of Psychiatry, 55 Fruit St. Boston, MA, USA
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  • For correspondence: emacosko@broadinstitute.org
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Abstract

Midbrain dopamine (DA) neurons in the substantia nigra pars compacta (SNpc) project widely throughout the central nervous system, playing critical roles in voluntary movements, reward processing, and working memory. Many of these neurons are highly sensitive to neurodegeneration in Parkinson’s Disease (PD), and their loss correlates strongly with the pathognomonic symptoms. To characterize these populations molecularly, we developed a protocol to enrich and transcriptionally profile DA neuron nuclei from postmortem human SNpc of both PD patients and matched controls. We identified a total of ten distinct populations, including one that was primate-specific. A single subtype, marked by the gene AGTR1, was highly susceptible to degeneration, and was enriched for expression of genes associated with PD in genetic studies, suggesting many risk loci act within this subtype to influence its neurodegeneration. The AGTR1 subtype also showed the strongest upregulation of TP53 and its downstream targets, nominating a potential pathway of degeneration in vivo. The transcriptional characterization of differentially disease-vulnerable DA neurons in the SNpc will inform the development of laboratory models, enable the nomination of novel disease biomarkers, and guide further studies of pathogenic disease mechanisms.

Competing Interest Statement

The authors have declared no competing interest.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license.
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Posted June 16, 2021.
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A molecular census of midbrain dopaminergic neurons in Parkinson’s disease
Tushar Kamath, Abdulraouf Abdulraouf, SJ Burris, Vahid Gazestani, Naeem Nadaf, Charles Vanderburg, Evan Z Macosko
bioRxiv 2021.06.16.448661; doi: https://doi.org/10.1101/2021.06.16.448661
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A molecular census of midbrain dopaminergic neurons in Parkinson’s disease
Tushar Kamath, Abdulraouf Abdulraouf, SJ Burris, Vahid Gazestani, Naeem Nadaf, Charles Vanderburg, Evan Z Macosko
bioRxiv 2021.06.16.448661; doi: https://doi.org/10.1101/2021.06.16.448661

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