Differential Co-Expression between α-Synuclein and IFN-γ Signaling Genes across Development and in Parkinson’s Disease

Liscovitch, Noa; French, Leon

doi:10.1371/journal.pone.0115029

Cited by 37 publications

(29 citation statements)

References 49 publications

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“…Module M47 was negatively co-expressed with SNCA. Notably, a significant loss of negative co-expression between SNCA and interferon-gamma genes in the substantia nigra has been demonstrated in PD patients as compared to controls 41 . This loss may result from a downregulation of genes within M47 in the substantia nigra of PD patients, similarly as was observed in blood transcriptomics of PD [38][39][40] .…”

Section: Discussionmentioning

confidence: 97%

Transcriptomic signatures of brain regional vulnerability to Parkinson’s disease

et al. 2020

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The molecular mechanisms underlying caudal-to-rostral progression of Lewy body pathology in Parkinson's disease remain poorly understood. Here, we identified transcriptomic signatures across brain regions involved in Braak Lewy body stages in non-neurological adults from the Allen Human Brain Atlas. Among the genes that are indicative of regional vulnerability, we found known genetic risk factors for Parkinson's disease: SCARB2, ELOVL7, SH3GL2, SNCA, BAP1, and ZNF184. Results were confirmed in two datasets of nonneurological subjects, while in two datasets of Parkinson's disease patients we found altered expression patterns. Co-expression analysis across vulnerable regions identified a module enriched for genes associated with dopamine synthesis and microglia, and another module related to the immune system, blood-oxygen transport, and endothelial cells. Both were highly expressed in regions involved in the preclinical stages of the disease. Finally, alterations in genes underlying these region-specific functions may contribute to the selective regional vulnerability in Parkinson's disease brains.

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Section: Discussionmentioning

confidence: 97%

Transcriptomic signatures of brain regional vulnerability to Parkinson’s disease

et al. 2020

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“…Module M47 was negatively co-expressed with SNCA. Notably, a significant loss of negative co-expression between SNCA and interferon-gamma genes in the substantia nigra has been demonstrated in PD patients as compared to controls 42 . This loss may result from a downregulation of genes within M47 in the substantia nigra of PD patients, similarly as was observed in PD blood transcriptomics 39–41 .…”

Section: Discussionmentioning

confidence: 97%

Transcriptomic signatures of brain regional vulnerability to Parkinson’s disease

Keo

Mahfouz

Ingrassia

et al. 2019

Preprint

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25The molecular mechanisms underlying the caudal-to-rostral progression of Lewy body pathology in 26Parkinson's disease (PD) remain poorly understood. Here, we aimed to unravel transcriptomic signatures 27 across brain regions involved in Braak Lewy body stages in non-neurological controls and PD donors. 28Using human postmortem brain datasets of non-neurological adults from the Allen Human Brain Atlas, we 29 identified expression patterns related to PD progression, including genes found in PD genome-wide 30 associations studies: SNCA, ZNF184, BAP1, SH3GL2, ELOVL7, and SCARB2. We confirmed these 31 patterns in two datasets of non-neurological subjects (Genotype-Tissue Expression project and UK Brain 32 Expression Consortium) and found altered patterns in two datasets of PD patients. Additionally, co-33 expression analysis across vulnerable regions identified two modules associated with dopamine 34 synthesis, the motor and immune system, blood-oxygen transport, and contained microglial and 35 endothelial cell markers, respectively. Alterations in genes underlying these region-specific functions may 36 contribute to the selective regional vulnerability in PD brains. 37 38 3 Background 39 Parkinson's disease (PD) is characterized by a temporal caudal-rostral progression of Lewy body (LB) 40 pathology across a selected set of nuclei in the brain 1 . The distribution pattern of LB pathology is divided 41 into six Braak stages based on accumulation of the protein α-synucleinthe main component of LBs and 42 Lewy neuritesin the brainstem, limbic and neocortical regions 1 . Different hypotheses have been 43 brought forward to explain the evolving LB pathology across the brain, including: retrograde transport of 44 pathological α-synuclein via neuroanatomical networks, α-synuclein's prion-like behavior, and cell-or 45 region-autonomous factors 2,3 . Yet, the mechanisms underlying the selective vulnerability of brain regions 46 to LB pathology remains poorly understood, limiting the ability to diagnose and treat PD. 47 Multiplications of the SNCA gene encoding α-synuclein are relatively common in autosomal dominant PD 48and SNCA dosage has been linked to the severity of PD 4,5 . For other PD-associated variants, e.g. GBA 49and LRRK2, their role in progressive α-synuclein accumulation is less clear, although they have been 50 associated with mitochondrial (dys)function and/or protein degradation pathways [6][7][8] . On the other hand, 51 transcriptomic changes between PD and non-neurological controls of selected brain regions, e.g. the 52 substantia nigra, have identified several molecular mechanisms underlying PD pathology, including 53 synaptic vesicle endocytosis [9][10][11] . However, post-mortem human brain tissue of well-characterized PD 54 patients and controls is scarce, usually focuses on a select number of brain regions, and have a limited 55 coverage of patients with different Braak LB stages, resulting in low concordance of findings across 56 different studies 12 . 57Spatial gene expression patterns in the human ...

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“…However, increasing evidence indicate that dysregulation of IFN signaling plays a role in ageing and neurodegenerative disease processes 2,3,4 . With respect to PD, genetic and functional studies have identified a link between IFN-γ and disease 5,6,11,13,14,15 . There is also considerable evidence that PD genes can synergize with inflammatory triggers in determining disease risk 16,49,50 .…”

Section: Discussionmentioning

confidence: 99%

“…Supporting a possible role of IFN-γ in the disease process, increased levels of IFN-γ in the serum, as well as increased production of IFN-γ by peripheral CD4+ T cells, have been detected in PD patients compared to healthy controls 11,12 . Moreover, a significant co-expression of α -synuclein and IFN-γ has been found within the substantia nigra of PD patients 13 . Experimental models also support this connection, whereby IFN-γ has been linked to selective, progressive, DA neurodegeneration in rodents 11,14,15 .…”

Section: Introductionmentioning

confidence: 97%

Interferon-γ signaling synergizes with LRRK2 in human neurons and microglia

Cicco

Ivanyuk

Haq

et al. 2020

Preprint

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Increasing evidence suggests a role for interferons (IFNs) in neurodegeneration.Parkinson's disease (PD) associated kinase LRRK2 has been implicated in IFN type II (IFN) response in infections and nigral neuronal loss. However, whether and how LRRK2 synergizes with IFN-γ still remains unclear. Here, we employed dopaminergic (DA) neurons and microglia differentiated from patient induced pluripotent stem cells to unravel the role of IFN-γ in LRRK2-PD. We show that IFN-γ induces LRRK2 expression in both DA neurons and microglial cells. LRRK2-G2019S, the most common PD-associated mutation, sensitizes DA neurons to IFN-γ by decreasing AKT phosphorylation. IFN-γ suppresses NFAT activity in both neurons and microglia and synergistically enhances LRRK2-induced defects of NFAT activation.Furthermore, LRRK2-G2019S negatively regulates NFAT via calcium and microtubule dynamics. Importantly, we uncover functional consequences of the reduction of NFAT activity in both cell types, namely defects of neurite elongation and alteration of microglial activation profile and motility. We propose that synergistic IFN-γ/LRRK2 activation serves as a direct link between inflammation and neurodegeneration in PD.

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Differential Co-Expression between α-Synuclein and IFN-γ Signaling Genes across Development and in Parkinson’s Disease

Cited by 37 publications

References 49 publications

Transcriptomic signatures of brain regional vulnerability to Parkinson’s disease

Transcriptomic signatures of brain regional vulnerability to Parkinson’s disease

Transcriptomic signatures of brain regional vulnerability to Parkinson’s disease

Interferon-γ signaling synergizes with LRRK2 in human neurons and microglia

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