Dysregulation of mitochondrial and proteolysosomal genes in Parkinson’s disease myeloid cells

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 hypothesize that PD susceptibility genes modulate disease risk by influencing gene expression within immune cells. To ad...

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Published inNature aging Vol. 1; no. 9; pp. 850 - 863
Main Authors Navarro, Elisa, Udine, Evan, Lopes, Katia de Paiva, Parks, Madison, Riboldi, Giulietta, Schilder, Brian M., Humphrey, Jack, Snijders, Gijsje J. L., Vialle, Ricardo A., Zhuang, Maojuan, Sikder, Tamjeed, Argyrou, Charalambos, Allan, Amanda, Chao, Michael J., Farrell, Kurt, Henderson, Brooklyn, Simon, Sarah, Raymond, Deborah, Elango, Sonya, Ortega, Roberto A., Shanker, Vicki, Swan, Matthew, Zhu, Carolyn W., Ramdhani, Ritesh, Walker, Ruth H., Tse, Winona, Sano, Mary, Pereira, Ana C., Ahfeldt, Tim, Goate, Alison M., Bressman, Susan, Crary, John F., de Witte, Lotje, Frucht, Steven, Saunders-Pullman, Rachel, Raj, Towfique
Format Journal Article
LanguageEnglish
Published United States Nature Publishing Group 01.09.2021
Subjects
Age
Aging
Brain - metabolism
Brain research
Disease
Gene expression
Gene Expression Profiling
Humans
Hypotheses
Medicine
Monocytes - metabolism
Neurology
Parkinson Disease - genetics
Pathology
Transcriptome
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Summary: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 hypothesize that PD susceptibility genes modulate disease risk by influencing gene expression within immune cells. To address this, we have generated transcriptomic profiles of monocytes from 230 individuals with sporadic PD and healthy subjects. We observed a 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, is 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.
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T.R conceived the study. T.R, E.N and E.U led the project, designed and performed the experiments and analysis and wrote the manuscript. K.P.L. performed co-expression network and microglial transcriptomic analysis. M.P. and E.N. optimized experimental approach. M.P., M.Z and A.A. performed experimental isolations. B.M.S. and J.H. performed single-cell and splicing analyses, respectively. T.S., C.A., B.H. and S.S. contributed with clinical coordination. R.A.V. contributed to data analyses. G.R. and S.F. were responsible for the implementation and recruitment of movement disorder patients in NYUMD and BPMD. M.C. contributed to genetic and population characterization. D.R., S.E., R.A.O., V.S., M.S., S.B. and R.S-P. contributed with recruitment and clinical characterization of patients from MSBI; C.W.Z. and M.S. contributed to recruitment donors from ADRC; A.C.P. implemented recruitment of donors from CCH; R.R., R.H.W. and W.T. helped in recruitment of patients from BPMD. T.A. and A.M.G. helped with intellectual discussion and interpretation of the results. K.F. R.H.W. and J.F.C. contributed to brain sample collection. G.J.L.S. and L.dW. contributed to microglial isolation and characterization. All authors read and approved the final manuscript.
These authors contributed equally
Author contributions
ISSN:2662-8465
2662-8465
DOI:10.1038/s43587-021-00110-x