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Transcriptome deregulation of peripheral monocytes in GBA-related Parkinson's disease [article]

Giulietta Maria Riboldi, Ricardo A Vialle, Elisa Navarro, Evan Udine, Katia de Paiva Lopes, Amanda Allan, Madison Park, Brooklyn Henderson, Kelly Astudillo, Charalambos Argyrou,, Maojuan Zhuang, Tamjeed Sikder (+9 others)
2021 medRxiv   pre-print

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https://web.archive.org/web/20220204081936/https://www.medrxiv.org/content/medrxiv/early/2021/12/24/2021.12.22.21267952.full.pdf

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Genetic mutations in the beta-glucocerebrosidase (GCase), GBA gene, represent the major genetic risk factor for Parkinson's disease (PD). The function of the GBA gene is at the crossroads between the endo-lysosomal pathway and the immune response, two important mechanisms involved in the pathogenesis of PD. However, modifiers of GBA penetrance have not yet been fully elucidated. Methods: we characterized the transcriptomic profiles of circulating monocytes and whole blood in a population of
more » ... ents with PD and healthy controls (CTRL) with (PD/GBA and CTRL/GBA) and without GBA variants (iPD and CTRL) (monocytes: n = 56 iPD, 66 CTRL, 23 PD/GBA, 13 CTRL/GBA; whole blood: n = 616 iPD, 362 CTRLs, 127 PD/GBA, 165 CTRL/GBA). Differential expression analysis, pathways enrichment analysis, and outliers detections were performed. Ultrastructural characterization of isolated CD14+ monocytes in the four groups was also performed through electron microscopy. Results: We observed hundreds of differentially expressed genes and dysregulated pathways when comparing manifesting and non-manifesting GBA mutation carriers. Specifically, when compared to idiopathic PD, GBA-PD showed dysregulation in genes involved in alpha-synuclein degradation, aging and amyloid processing (i.e. SNCA, LMNA). Gene-based outlier analysis confirmed the involvement of lysosomal, membrane trafficking, and mitochondrial processing in manifesting compared to nonmanifesting GBA-carriers, as also observed at the ultrastructural levels. Conclusions: Overall, our transcriptomic analysis of primary monocytes identified gene targets and biological processes that can help in understanding the pathogenic mechanisms associated with GBA mutations in the context of PD.
doi:10.1101/2021.12.22.21267952 fatcat:wumj4oiegnayno6n45jfkymwzq
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Giulietta Maria Riboldi, Ricardo A Vialle, Elisa Navarro, Evan Udine, Katia de Paiva Lopes, Amanda Allan, Madison Park, Brooklyn Henderson, Kelly Astudillo, Charalambos Argyrou,, Maojuan Zhuang, Tamjeed Sikder, Oriol J Narics, Shilpa Dilip Kumar, William Janssen, Allison Sowa, Giacomo P Comi, Alessio Di Fonzo, John F Crary, Steven J Frucht, Towfique Raj. "Transcriptome deregulation of peripheral monocytes in GBA-related Parkinson's disease." medRxiv (2021)