TY - JOUR
T1 - Dysregulation of mitochondrial and proteolysosomal genes in Parkinson’s disease myeloid cells
AU - Navarro, Elisa
AU - Udine, Evan
AU - Lopes, Katia de Paiva
AU - Parks, Madison
AU - Riboldi, Giulietta
AU - Schilder, Brian M.
AU - Humphrey, Jack
AU - Snijders, Gijsje J.L.
AU - Vialle, Ricardo A.
AU - Zhuang, Maojuan
AU - Sikder, Tamjeed
AU - Argyrou, Charalambos
AU - Allan, Amanda
AU - Chao, Michael J.
AU - Farrell, Kurt
AU - Henderson, Brooklyn
AU - Simon, Sarah
AU - Raymond, Deborah
AU - Elango, Sonya
AU - Ortega, Roberto A.
AU - Shanker, Vicki
AU - Swan, Matthew
AU - Zhu, Carolyn W.
AU - Ramdhani, Ritesh
AU - Walker, Ruth H.
AU - Tse, Winona
AU - Sano, Mary
AU - Pereira, Ana C.
AU - Ahfeldt, Tim
AU - Goate, Alison M.
AU - Bressman, Susan
AU - Crary, John F.
AU - de Witte, Lotje
AU - Frucht, Steven
AU - Saunders-Pullman, Rachel
AU - Raj, Towfique
N1 - Funding Information:
We thank the study participants for providing blood samples and for their generous gifts of brain donation to the MyND study. We thank the Netherlands Brain Bank and the Neuropathology Brain Bank & Research Core at Mount Sinai for assistance in collecting human brain samples. We thank the Flow Cytometry Core and the Human Immune Monitoring Center at Icahn School of Medicine at Mount Sinai (ISMMS) for optimization of cell isolations; Genewiz Inc. for RNA-seq; C. Proukakis for feedback on the manuscript; S. Kim-Schulze for help in optimizing PBMC and monocyte isolation; Y.-C. Wang for help with processing of RNA-seq data; J. Fernandez-Lopez for help with data analysis; members of the Ronald Loeb Center for AD for helpful discussions; and research participants and employees of 23andMe who contributed to PD GWAS. Data used in the preparation of this article were obtained from the AMP-PD Knowledge Platform. AMP-PD—a public–private partnership—is managed by the US National Institutes of Health (NIH) and funded by Celgene, GSK, the Michael J. Fox Foundation for Parkinson’s Research, the National Institute of Neurological Disorders and Stroke, Pfizer, Sanofi and Verily. PPMI—a public–private partnership—is funded by the Michael J. Fox Foundation for Parkinson’s Research and funding partners (names of all PPMI funding partners can be found at www.ppmi-info.org/fundingpartners ). The PPMI Investigators did not participate in reviewing the data analysis or content of the manuscript. For up-to-date information on the study, visit www.ppmi-info.org . This work was supported in part through the computational resources and staff expertise provided by Scientific Computing at the ISMMS. T.R. was supported by grants from the Michael J. Fox Foundation (nos. 4899 and 16743) and NIH (nos. NINDS R01-NS116006, NINDS U01-NS120256, NIA R01-AG054005, NIA R21-AG063130 and NIA U01 P50-AG005138). R.S-P. is supported by grants from the NIH (nos. NINDS U01-NS107016 and NINDS U01-NS094148-01) and Bigglesworth Family Foundation. K.F. is supported by NIH (no. F32 AG056098). E.N. is supported by a fellowship from the Ramon Areces Foundation (Spain). The research reported in this paper was additionally supported by the Office of Research Infrastructure of the NIH under award nos. S10OD018522 and S10OD026880.
Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2021/9
Y1 - 2021/9
N2 - An increasing number of identified Parkinson’s disease (PD) risk loci contain genes highly expressed in innate immune cells, yet their role in pathology is not understood. We hypothesized that PD susceptibility genes modulate disease risk by influencing gene expression within immune cells. To address this, we generated transcriptomic profiles of monocytes from healthy subjects and 230 individuals with sporadic PD. We observed dysregulation of mitochondrial and proteasomal pathways. We also generated transcriptomic profiles of primary microglia from brains of 55 subjects and observed discordant transcriptomic signatures of mitochondrial genes in PD monocytes and microglia. We further identified 17 PD susceptibility genes whose expression, relative to each risk allele, was altered in monocytes. These findings reveal widespread transcriptomic alterations in PD monocytes, with some being distinct from microglia, and facilitate efforts to understand the roles of myeloid cells in PD as well as the development of biomarkers.
AB - An increasing number of identified Parkinson’s disease (PD) risk loci contain genes highly expressed in innate immune cells, yet their role in pathology is not understood. We hypothesized that PD susceptibility genes modulate disease risk by influencing gene expression within immune cells. To address this, we generated transcriptomic profiles of monocytes from healthy subjects and 230 individuals with sporadic PD. We observed dysregulation of mitochondrial and proteasomal pathways. We also generated transcriptomic profiles of primary microglia from brains of 55 subjects and observed discordant transcriptomic signatures of mitochondrial genes in PD monocytes and microglia. We further identified 17 PD susceptibility genes whose expression, relative to each risk allele, was altered in monocytes. These findings reveal widespread transcriptomic alterations in PD monocytes, with some being distinct from microglia, and facilitate efforts to understand the roles of myeloid cells in PD as well as the development of biomarkers.
UR - http://www.scopus.com/inward/record.url?scp=85121661114&partnerID=8YFLogxK
U2 - 10.1038/s43587-021-00110-x
DO - 10.1038/s43587-021-00110-x
M3 - Article
AN - SCOPUS:85121661114
SN - 2662-8465
VL - 1
SP - 850
EP - 863
JO - Nature Aging
JF - Nature Aging
IS - 9
ER -