Molecular profiling of human substantia nigra identifies diverse neuron types associated with vulnerability in Parkinson’s disease-Reference-Cited by-同舟云学术

Molecular profiling of human substantia nigra identifies diverse neuron types associated with vulnerability in Parkinson’s disease

Published:2024-01-12 Issue:2 Volume:10 Page:
ISSN:2375-2548
Container-title:Science Advances
language:en
Short-container-title:Sci. Adv.

Author:

Wang Qian¹²³⁴⁵^ORCID,Wang Minghui¹⁵⁶^ORCID,Choi Insup²³⁴^ORCID,Sarrafha Lily²³⁴^ORCID,Liang Marianna²³⁴^ORCID,Ho Lap¹⁵⁶^ORCID,Farrell Kurt³⁴⁷^ORCID,Beaumont Kristin G.¹^ORCID,Sebra Robert¹⁶⁸,De Sanctis Claudia⁹^ORCID,Crary John F.³⁴⁷⁹¹⁰,Ahfeldt Tim³¹¹¹²^ORCID,Blanchard Joel³¹¹¹²^ORCID,Neavin Drew¹³^ORCID,Powell Joseph¹³¹⁴^ORCID,Davis David A.¹⁵^ORCID,Sun Xiaoyan¹⁵,Zhang Bin¹⁵⁶¹⁶^ORCID,Yue Zhenyu²³⁴¹⁷^ORCID

Affiliation:

1. Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA.

2. Department of Neurology, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA.

3. Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, 1470 Madison Avenue, New York, NY 10029, USA.

4. Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, 1470 Madison Avenue, New York, NY 10029, USA.

5. Mount Sinai Center for Transformative Disease Modeling, Icahn School of Medicine at Mount Sinai, 1470 Madison Avenue, New York, NY 10029, USA.

6. Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA.

7. Department of Pathology, Icahn School of Medicine at Mount Sinai, 1470 Madison Avenue, New York, NY 10029, USA.

8. Sema4, a Mount Sinai venture, Stamford, CT 06902, USA.

9. Neuropathology Brain Bank & Research CoRE, Icahn School of Medicine at Mount Sinai, 1470 Madison Avenue, New York, NY 10029, USA.

10. Department of Artificial Intelligence & Human Health, Icahn School of Medicine at Mount Sinai, 1470 Madison Avenue, NY 10029, USA.

11. Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA.

12. Ronald Loeb Alzheimer’s Disease Center, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA.

13. Garvan-Weizmann Centre for Cellular Genomics, Garvan Institute for Medical Research, 384 Victoria Street, Sydney 2010, Australia.

14. UNSW Cellular Genomics Futures Institute, University of New South Wales, Kensington, Sydney 2052, Australia.

15. Department of Neurology, Evelyn F. McKnight Brain Institute, Brain Endowment Bank, University of Miami Miller School of Medicine, Miami, FL 33136, USA.

16. Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA.

17. The Center for Parkinson’s Disease Neurobiology, Icahn School of Medicine at Mount Sinai, 1470 Madison Avenue, New York, NY 10029, USA.

Abstract

Parkinson’s disease (PD) is characterized pathologically by the loss of dopaminergic (DA) neurons in the substantia nigra (SN). Whether cell types beyond DA neurons in the SN show vulnerability in PD remains unclear. Through transcriptomic profiling of 315,867 high-quality single nuclei in the SN from individuals with and without PD, we identified cell clusters representing various neuron types, glia, endothelial cells, pericytes, fibroblasts, and T cells and investigated cell type–dependent alterations in gene expression in PD. Notably, a unique neuron cluster marked by the expression of RIT2 , a PD risk gene, also displayed vulnerability in PD. We validated RIT2 -enriched neurons in midbrain organoids and the mouse SN. Our results demonstrated distinct transcriptomic signatures of the RIT2 -enriched neurons in the human SN and implicated reduced RIT2 expression in the pathogenesis of PD. Our study sheds light on the diversity of cell types, including DA neurons, in the SN and the complexity of molecular and cellular changes associated with PD pathogenesis.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

Link

https://www.science.org/doi/pdf/10.1126/sciadv.adi8287

Reference64 articles.

1. The Noradrenergic System in Parkinson’s Disease

2. On Cell Loss and Selective Vulnerability of Neuronal Populations in Parkinson's Disease

3. Identification of novel risk loci, causal insights, and heritable risk for Parkinson's disease: a meta-analysis of genome-wide association studies

4. The genetic architecture of Parkinson's disease

5. A meta-analysis of genome-wide association studies identifies 17 new Parkinson's disease risk loci