RNA sequencing of whole blood reveals early alterations in immune cells and gene expression in Parkinson’s disease

Craig, David W.; Hutchins, Elizabeth; Violich, Ivo; Alsop, Eric; Gibbs, J. Raphael; Levy, Shawn; Robison, Madison; Prasad, Nripesh; Foroud, Tatiana; Crawford, Karen; Toga, Arthur W.; Whitsett, Timothy G.; S, Kim; Casey, Bradford; Reimer, Alyssa; Frasier, Mark; Kern, Fabian; Fehlmann, Tobias; Keller, Andreas; Cookson, Mark; Hutten, Samantha J.; Keuren‐Jensen, Kendall Van

doi:10.1038/s43587-021-00088-6

Cited by 46 publications

(58 citation statements)

References 63 publications

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“…1 ). The lower lymphocyte count and higher neutrophils in prodromal and clinical PD have been also corroborated in a recent study using samples from the Parkinson’s Progression Marker Initiative (PPMI) cohort ( https://www.ppmi-info.org ), where higher expression of neutrophil enriched transcripts further validated the increased neutrophil population [ 41 ]. This increase was greatest during prodromal (high-risk) PD and once elevated it remained so during the disease.…”

Section: Evidence From Retrospective Studies For Immune Changes In Pr...mentioning

confidence: 64%

Neuroinflammation and Immune Changes in Prodromal Parkinson’s Disease and Other Synucleinopathies

Terkelsen

Klæstrup

Hvingelby

et al. 2022

JPD

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Multiple lines of clinical and pre-clinical research support a pathogenic role for neuroinflammation and peripheral immune system dysfunction in Parkinson’s disease. In this paper, we have reviewed and summarised the published literature reporting evidence of neuroinflammation and peripheral immune changes in cohorts of patients with isolated REM sleep behaviour disorder and non-manifesting carriers of GBA or LRRK2 gene mutations, who have increased risk for Parkinsonism and synucleinopathies, and could be in the prodromal stage of these conditions. Taken together, the findings of these studies suggest that the early stages of pathology in Parkinsonism involve activation of both the central and peripheral immune systems with significant crosstalk. We consider these findings with respect to those found in patients with clinical Parkinson’s disease and discuss their possible pathological roles. Moreover, those factors possibly associated with the immune response, such as the immunomodulatory role of the affected neurotransmitters and the changes in the gut-brain axis, are also considered.

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Section: Evidence From Retrospective Studies For Immune Changes In Pr...mentioning

confidence: 64%

Neuroinflammation and Immune Changes in Prodromal Parkinson’s Disease and Other Synucleinopathies

Terkelsen

Klæstrup

Hvingelby

et al. 2022

JPD

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“…We performed gene expression analysis using longitudinal RNA-seq data of the PPMI 62 . In particular, we collected all samples of each patient.…”

Section: Gene Expression Analysismentioning

confidence: 99%

Identification of Parkinson PACE subtypes and repurposing treatments through integrative analyses of multimodal clinical progression, neuroimaging, genetic, and transcriptomic data

Hou

Brendel

et al. 2021

Preprint

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The Parkinson's disease (PD) is a heterogeneous neurodegenerative disease, of which the etiological and pathological mechanisms remain unclear to date. PD has been associated with diverse movement dysfunctions and non-motor symptoms (i.e., symptom heterogeneity) and progression patterns of these symptoms differ from patient to patient (i.e., progression heterogeneity). To address these, the present investigation aims at comprehensively considering full progression course of early PDs to identify subtypes, each of which can reflect unique PD progression pattern. We retrospectively analyzed the Parkinson's Progression Markers Initiative (PPMI) and the Parkinson Disease Biomarkers Program (PDBP) as the development and validation cohorts, respectively. An unsupervised deep learning model was built to model progression trajectories in diverse clinical manifestations and cerebrospinal fluid (CSF) biomarkers to produce a representation vector for each patient, encoding his/her symptom progression profile. Then by performing clustering analysis on the patients' representation vectors, we identified three subtypes with distinct PD progression patterns in the PPMI cohort: Subtype I, mild baseline severity and mild symptom progression; mild baseline severity and moderate progression; and Subtype III, rapid symptom progression. Replication in the PDBP validation cohort demonstrated reproducibility of the subtypes. After that, we explored demographic factors, CSF biomarkers, neuroimaging biomarkers in brain regional atrophy, and genetic factors of the subtypes. Last, to enhance usability of the subtypes, predictive model of subtypes that relies on data at baseline and 1-year follow-up was trained. In conclusion, the identified subtypes revealed significant symptom progression patterns of PDs. Patients with similar baseline severities can even suffer from different progression pattern, leading to distinct prognosis. Demographic factors, biomarkers, and genetic components of the subtypes suggested distinct biological mechanisms and pathways potentially leading to those progression patterns. Our findings may benefit pathophysiological study, clinical practice, and clinical trials to advance PD.

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“…GCase, the enzyme encoded by the PD-genetic risk factor GBA , is important for the metabolic processes of scavenger cells such as monocytes and macrophages. Compared to previous works that performed unbiased transcriptomic analysis comparing PD and CTRL subjects, we report here the first transcriptomic analysis in whole blood and CD14+ monocytes stratified by GBA mutation status [ 41 , 45 ]. We found that expression profiles of patients with PD and GBA variants were significantly different from both idiopathic PD patients and non-manifesting carriers (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…For the PPMI cohort, blood samples were centrally collected and processed as reported by the study’s related documentation ( www.ppmi-info.org ) and as previously reported [ 45 ]. Cell type composition (percentage of neutrophils, lymphocytes, monocytes, basophils, eosinophils) was provided as well with metadata.…”

Section: Methodsmentioning

confidence: 99%

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Transcriptome deregulation of peripheral monocytes and whole blood in GBA-related Parkinson’s disease

Riboldi

Vialle

Navarro

et al. 2022

Mol Neurodegeneration

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Background Genetic mutations in beta-glucocerebrosidase (GBA) represent the major genetic risk factor for Parkinson’s disease (PD). GBA participates in both 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 in a population of patients with PD and healthy controls (CTRL) with and without GBA variants (n = 23 PD/GBA, 13 CTRL/GBA, 56 PD, 66 CTRL) and whole blood (n = 616 PD, 362 CTRL, 127 PD/GBA, 165 CTRL/GBA). Differential expression analysis, pathway enrichment analysis, and outlier detection 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, PD/GBA showed dysregulation in genes involved in alpha-synuclein degradation, aging and amyloid processing. Gene-based outlier analysis confirmed the involvement of lysosomal, membrane trafficking, and mitochondrial processing in manifesting compared to non-manifesting GBA-carriers, as also observed at the ultrastructural levels. Transcriptomic results were only partially replicated in an independent cohort of whole blood samples, suggesting cell-type specific changes. 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.

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RNA sequencing of whole blood reveals early alterations in immune cells and gene expression in Parkinson’s disease

Cited by 46 publications

References 63 publications

Neuroinflammation and Immune Changes in Prodromal Parkinson’s Disease and Other Synucleinopathies

Neuroinflammation and Immune Changes in Prodromal Parkinson’s Disease and Other Synucleinopathies

Identification of Parkinson PACE subtypes and repurposing treatments through integrative analyses of multimodal clinical progression, neuroimaging, genetic, and transcriptomic data

Transcriptome deregulation of peripheral monocytes and whole blood in GBA-related Parkinson’s disease

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