LRRK2 G2019S variant is associated with transcriptional changes in Parkinson's disease human myeloid cells under proinflammatory environment.

Autor:	Navarro E; Nash Family Department of Neuroscience & Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America.; Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America.; Department of Genetics and Genomic Sciences & Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America.; Estelle and Daniel Maggin Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America.; Instituto Universitario de Investigacion en Neuroquimica, Departamento de Bioquimica y Biologia Molecular, Facultad de Medicina, Universidad Complutense, Madrid, Spain.; Centro de Investigacion Biomedica en Red de Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain.; Instituto Ramon y Cajal de Investigacion Sanitaria (IRYCIS), Madrid, Spain., Efthymiou AG; Nash Family Department of Neuroscience & Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America.; Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America.; Department of Genetics and Genomic Sciences & Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America., Parks M; Nash Family Department of Neuroscience & Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America.; Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America.; Department of Genetics and Genomic Sciences & Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America.; Estelle and Daniel Maggin Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America., Riboldi GM; The Marlene and Paolo Fresco Institute for Parkinson's Disease and Movement Disorders, New York University Langone Health, New York, NY, USA., Vialle RA; Nash Family Department of Neuroscience & Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America.; Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America.; Department of Genetics and Genomic Sciences & Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America.; Estelle and Daniel Maggin Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America.; Rush Alzheimer's Disease Center, Rush University Medical Center; Chicago, IL, 60612, USA.; Department of Neurological Sciences, Rush University Medical Center; Chicago, IL, 60612, USA., Udine E; Nash Family Department of Neuroscience & Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America.; Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America.; Department of Genetics and Genomic Sciences & Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America.; Estelle and Daniel Maggin Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America., Muller BZ; Nash Family Department of Neuroscience & Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America.; Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America.; Department of Genetics and Genomic Sciences & Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America.; Estelle and Daniel Maggin Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America., Humphrey J; Nash Family Department of Neuroscience & Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America.; Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America.; Department of Genetics and Genomic Sciences & Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America.; Estelle and Daniel Maggin Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America., Allan A; Nash Family Department of Neuroscience & Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America.; Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America.; Department of Genetics and Genomic Sciences & Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America.; Estelle and Daniel Maggin Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America., Argyrou CC; Nash Family Department of Neuroscience & Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America.; Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America.; Department of Genetics and Genomic Sciences & Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America.; Estelle and Daniel Maggin Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America., Lopes KP; Nash Family Department of Neuroscience & Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America.; Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America.; Department of Genetics and Genomic Sciences & Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America.; Estelle and Daniel Maggin Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America.; Rush Alzheimer's Disease Center, Rush University Medical Center; Chicago, IL, 60612, USA.; Department of Neurological Sciences, Rush University Medical Center; Chicago, IL, 60612, USA., Münch A; Nash Family Department of Neuroscience & Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America.; Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America.; Department of Genetics and Genomic Sciences & Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America., Raymond D; Estelle and Daniel Maggin Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America.; Department of Neurology, Mount Sinai Beth Israel, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Sachdev R; Estelle and Daniel Maggin Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America.; Department of Neurology, Mount Sinai Beth Israel, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Shanker VL; Estelle and Daniel Maggin Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America.; Department of Neurology, Mount Sinai Beth Israel, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Miravite J; Estelle and Daniel Maggin Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America.; Department of Neurology, Mount Sinai Beth Israel, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Katsnelson V; Estelle and Daniel Maggin Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America.; Department of Neurology, Mount Sinai Beth Israel, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Leaver K; Estelle and Daniel Maggin Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America.; Department of Neurology, Mount Sinai Beth Israel, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Frucht S; The Marlene and Paolo Fresco Institute for Parkinson's Disease and Movement Disorders, New York University Langone Health, New York, NY, USA., Bressman SB; Estelle and Daniel Maggin Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America.; Department of Neurology, Mount Sinai Beth Israel, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Marcora E; Nash Family Department of Neuroscience & Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America.; Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America.; Department of Genetics and Genomic Sciences & Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America., Saunders-Pullman R; Estelle and Daniel Maggin Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America.; Department of Neurology, Mount Sinai Beth Israel, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Goate A; Nash Family Department of Neuroscience & Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America.; Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America.; Department of Genetics and Genomic Sciences & Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America.; Estelle and Daniel Maggin Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America., Raj T; Nash Family Department of Neuroscience & Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America.; Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America.; Department of Genetics and Genomic Sciences & Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America.; Estelle and Daniel Maggin Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2024 May 31. Date of Electronic Publication: 2024 May 31.
DOI:	10.1101/2024.05.27.594821
Abstrakt:	The G2019S mutation in the leucine-rich repeat kinase 2 (LRRK2) gene is a major risk factor for the development of Parkinson's disease (PD). LRRK2, although ubiquitously expressed, is highly abundant in cells of the innate immune system. Given the importance of central and peripheral immune cells in the development of PD, we sought to investigate the consequences of the G2019S mutation on microglial and monocyte transcriptome and function. We have generated large-scale transcriptomic profiles of isogenic human induced microglial cells (iMGLs) and patient derived monocytes carrying the G2019S mutation under baseline culture conditions and following exposure to the proinflammatory factors IFNγ and LPS. We demonstrate that the G2019S mutation exerts a profound impact on the transcriptomic profile of these myeloid cells, and describe corresponding functional differences in iMGLs. The G2019S mutation led to an upregulation in lipid metabolism and phagolysosomal pathway genes in untreated and LPS/IFNγ stimulated iMGLs, which was accompanied by an increased phagocytic capacity of myelin debris. We also identified dysregulation of cell cycle genes, with a downregulation of the E2F4 regulon. Transcriptomic characterization of human-derived monocytes carrying the G2019S mutation confirmed alteration in lipid metabolism associated genes. Altogether, these findings reveal the influence of G2019S on the dysregulation of the myeloid cell transcriptome under proinflammatory conditions.
Databáze:	MEDLINE
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