Unravelling cell type specific response to Parkinson’s Disease at single cell resolution

Martirosyan, Araks; Pestana, Francisco; Hebestreit, Katja; Gasparyan, Hayk; Aleksanyan, Razmik; Poovathingal, Suresh; Marneffe, Catherine; Thal, Dietmar Rudolf; Kottick, A.; Hanson-Smith, Victor Joseph; Guelfi, Sebastian; Metzakopian, Emmanouil; Belgard, T. Grant

doi:10.1101/2023.01.04.522691

Cited by 4 publications

(14 citation statements)

References 56 publications

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“…scRNA-Seq Characterization of Immune Cell Clusters in Line 61-PFF Mice. Several scRNA-Seq studies point to the heterogeneity of cells involved in PD pathogenesis (51)(52)(53)(54). To identify cell-speci c contributions in the Line 61-PFF model, we performed scRNA-Seq on sorted CD45 + leukocytes obtained from Line 61 mice injected with PBS, monomer, PFF plus VH, or PFF plus AZD1480 (Supplemental Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Several scRNA-Seq studies have focused on T-cells isolated from the blood and cerebrospinal uid of PD patients, demonstrating the differentiation and expansion of peripheral CD8 + T-cells and CD4 + T-cells, as well as the interaction of peripheral CD4 + T-cells with endothelial cells in PD patients(53, 88, 89). A recent snRNA-Seq study revealed an increased frequency of T-cells within the SNpc from postmortem PD patients(52). However, little is known about the transcriptional features of T-cells in PD, especially Tcells in ltrating the CNS.…”

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confidence: 99%

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Suppression of the JAK/STAT Pathway Inhibits Neuroinflammation in the Line 61-PFF Mouse Model of Parkinson’s Disease

Hong,

Wang,

Menard

et al. 2024

Preprint

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Parkinson’s disease (PD) is characterized by neuroinflammation, progressive loss of dopaminergic neurons, and accumulation of a-synuclein (a-Syn) into insoluble aggregates called Lewy pathology. The Line 61 a-Syn mouse is an established preclinical model of PD; Thy-1 is used to promote human a-Syn expression, and features of sporadic PD develop at 9-18 months of age. To accelerate the PD phenotypes, we injected sonicated human a-Syn preformed fibrils (PFFs) into the striatum, which produced phospho-Syn (p-a-Syn) inclusions in the substantia nigra pars compacta and significantly increased MHC Class II-positive immune cells. Additionally, there was enhanced infiltration and activation of innate and adaptive immune cells in the midbrain. We then used this new model, Line 61-PFF, to investigate the effect of inhibiting the JAK/STAT signaling pathway, which is critical for regulation of innate and adaptive immune responses. After administration of the JAK1/2 inhibitor AZD1480, immunofluorescence staining showed a significant decrease in p-a-Syn inclusions and MHC Class II expression. Flow cytometry showed reduced infiltration of CD4+ T-cells, CD8+ T-cells, CD19+ B-cells, dendritic cells, macrophages, and endogenous microglia into the midbrain. Importantly, single-cell RNA-Sequencing analysis of CD45+ cells from the midbrain identified 9 microglia clusters, 5 monocyte/macrophage (MM) clusters, and 5 T-cell (T) clusters, in which potentially pathogenic MM4 and T3 clusters were associated with neuroinflammatory responses in Line 61-PFF mice. AZD1480 treatment reduced cell numbers and cluster-specific expression of the antigen-presentation genes H2-Eb1, H2-Aa, H2-Ab1, and Cd74 in the MM4 cluster and proinflammatory genes such as Tnf, Il1b, C1qa, and C1qc in the T3 cluster. Together, these results indicate that inhibiting the JAK/STAT pathway suppresses the activation and infiltration of innate and adaptive cells, reducing neuroinflammation in the Line 61-PFF mouse model.

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

Suppression of the JAK/STAT Pathway Inhibits Neuroinflammation in the Line 61-PFF Mouse Model of Parkinson’s Disease

Hong,

Wang,

Menard

et al. 2024

Preprint

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“…Glial cells from the PD midbrain showed enrichment for microglia in an activated state and astrocytes at the end of astrogliosis [36], while microglia from the SN showed transcriptional evidence for the cytokine-mediated signaling pathway that strengthened with advancing PD pathogenesis [56]. In fact, an independent snRNA-seq analysis identified a transcriptionally distinct microglia subtype overrepresented in the PD SN that showed differential expression of ST6GAL1, which has been shown to promote sustained signaling through the NFκB and JAK/ STAT inflammatory pathways [48,58]. Taken together, these snRNA-seq analyses of the PD midbrain support both the increase in immune cells and upregulation of immune responses uncovered by the differential gene expression signals associated with neuroinflammation that were observed at a bulk resolution.…”

Section: Glial Cells Activate Inflammatory Pathways In Pdmentioning

confidence: 97%

“…Second, an analysis of oligodendrocytes from the PD midbrain identified differentially expressed genes (DEG) in synaptic transmission pathways compared to non-PD controls, which coincided with a reduced fraction of myelinating oligodendrocytes in PD samples [36]. Third, an oligodendrocyte subtype, whose transcripts were enriched for processes linked to synapse organization, was found to be depleted in PD samples compared to non-PD controls [48]. Indeed, oligodendrocytes are critical in the maintenance of synaptic function in a healthy state [49], yet the snRNA-seq data suggest that a subset of oligodendrocytes lose their preservative functions in PD pathology.…”

Section: Synaptic Dysfunction May Contribute To Dan Susceptibility In Pdmentioning

confidence: 99%

“…The findings of bulk RNA-seq regarding neuroinflammatory pathways in the Parkinsonian brain are corroborated by snRNA-seq. snRNA-seq studies on the prefrontal cortex [52], SN [48,56,57], and midbrain [36] also found evidence of an increased inflammatory response in PD, highlighting the role of neuroinflammation in specific cell types. In the prefrontal cortex, snRNA-seq found a higher proportion of microglia and brain resident T cells in PD samples compared to non-PD controls [52], suggesting a neuroinflammatory response and supporting the changes in cell-type proportions observed through bulk RNA-seq of this brain region.…”

Section: Glial Cells Activate Inflammatory Pathways In Pdmentioning

confidence: 99%

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Transcriptomics of Human Brain Tissue in Parkinson’s Disease: a Comparison of Bulk and Single-cell RNA Sequencing

Fiorini,

Dilliott,

Thomas

et al. 2024

Mol Neurobiol

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Parkinson’s disease (PD) is a chronic and progressive neurodegenerative disease leading to motor dysfunction and, in some cases, dementia. Transcriptome analysis is one promising approach for characterizing PD and other neurodegenerative disorders by informing how specific disease events influence gene expression and contribute to pathogenesis. With the emergence of single-cell and single-nucleus RNA sequencing (scnRNA-seq) technologies, the transcriptional landscape of neurodegenerative diseases can now be described at the cellular level. As the application of scnRNA-seq is becoming routine, it calls to question how results at a single-cell resolution compare to those obtained from RNA sequencing of whole tissues (bulk RNA-seq), whether the findings are compatible, and how the assays are complimentary for unraveling the elusive transcriptional changes that drive neurodegenerative disease. Herein, we review the studies that have leveraged RNA-seq technologies to investigate PD. Through the integration of bulk and scnRNA-seq findings from human, post-mortem brain tissue, we use the PD literature as a case study to evaluate the compatibility of the results generated from each assay and demonstrate the complementarity of the sequencing technologies. Finally, through the lens of the PD transcriptomic literature, we evaluate the current feasibility of bulk and scnRNA-seq technologies to illustrate the necessity of both technologies for achieving a comprehensive insight into the mechanism by which gene expression promotes neurodegenerative disease. We conclude that the continued application of both assays will provide the greatest insight into neurodegenerative disease pathology, providing both cell-specific and whole-tissue level information.

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Single-cell transcriptomic changes in oligodendroglial lineage cells derived from Parkinson’s disease patient-iPSCs with LRRK2-G2019S mutation

Dehestani,

Kessler,

Karmali

et al. 2024

Preprint

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Despite extensive research, the contribution of the LRRK2 p.G2019S mutation to Parkinson’s disease (PD) remains unclear. Recent findings indicate oligodendrocytes (ODCs) and their progenitors are vulnerable in PD pathogenesis. Notably, oligodendrocyte precursor cells (OPCs) exhibit high endogenous expression ofLRRK2. We induced PD patient-iPSCs with the LRRK2 p.G2019S mutation into oligodendroglial lineages and performed single-cell RNA sequencing. Cell type composition analysis revealed an increase in OPCs, proliferating OPCs and ciliated ependymal cells in LRRK2 lines, all of which are characterized byLRRK2expression. Differential expression analysis revealed transcriptomic changes in several pathways, including down-regulation of genes related to myelin assembly in ODCs, semaphorin-plexin pathway in OPCs, and cilium movement in proliferating OPCs. Cell-cell communication analysis identified significant alterations in several signaling pathways including a deactivation of PSAP signaling and an activation of MIF signaling in LRRK2 lines. Additionally, we observed an overall increase in SEMA6 signaling communication in LRRK2 cell lines; however, OPCs derived from these LRRK2 lines specifically lost SEMA6 signaling due to a down-regulation ofSEMA6AandPLXNA2. Pseudotemporal trajectory analysis revealed thatSHHhad significantly altered expression along the pseudotime, accompanied by higher expression levels in LRRK2 lines. These findings highlight the need for a deep exploration of the complex interactions among semaphorin-plexin, sonic hedgehog and cilium pathways in PD. We envision that our work will serve as a valuable resource for uncovering potential targets in PD.

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Unravelling cell type specific response to Parkinson’s Disease at single cell resolution

Cited by 4 publications

References 56 publications

Suppression of the JAK/STAT Pathway Inhibits Neuroinflammation in the Line 61-PFF Mouse Model of Parkinson’s Disease

Suppression of the JAK/STAT Pathway Inhibits Neuroinflammation in the Line 61-PFF Mouse Model of Parkinson’s Disease

Transcriptomics of Human Brain Tissue in Parkinson’s Disease: a Comparison of Bulk and Single-cell RNA Sequencing

Single-cell transcriptomic changes in oligodendroglial lineage cells derived from Parkinson’s disease patient-iPSCs with LRRK2-G2019S mutation

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