Ten Unsolved Questions About Neuroinflammation in Parkinson's Disease

A key process of neurodegeneration in Parkinson’s disease (PD) is the transneuronal spreading of α-synuclein. Alpha-synuclein is a presynaptic protein that is implicated in the pathogenesis of PD and other synucleinopathies, where it forms, upon intracellular aggregation, pathological inclusions. Other hallmarks of PD include neurodegeneration and microgliosis in susceptible brain regions. Whether it is primarily transneuronal spreading of α-synuclein particles, inclusion formation, or other mechanisms, such as inflammation, that cause neurodegeneration in PD is unclear. We used spreading/aggregation of α-synuclein induced by intracerebral injection of α-synuclein preformed fibrils into the mouse brain to address this question. We performed quantitative histological analysis for α-synuclein inclusions, neurodegeneration, and microgliosis in different brain regions, and a gene expression profiling of the ventral midbrain, at two different timepoints after disease induction. We observed significant neurodegeneration and microgliosis in brain regions not only with, but also without α-synuclein inclusions. We also observed prominent microgliosis in injured brain regions that did not correlate with neurodegeneration nor with inclusion load. In longitudinal gene expression profiling experiments, we observed early and unique alterations linked to microglial mediated inflammation that preceded neurodegeneration, indicating an active role of microglia in inducing neurodegeneration. Our observations indicate that α-synuclein inclusion formation is not the major driver in the early phases of PD-like neurodegeneration, but that diffusible, oligomeric α-synuclein species, which induce unusual microglial reactivity, play a key role in this process. Our findings uncover new features of α-synuclein induced pathologies, in particular microgliosis, and point to the necessity of a broader view of the process of “prion-like spreading” of that protein.

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Section: Discussionmentioning

confidence: 70%

“…The relative contribution of these different processes to neuronal demise is unclear. Neuroinflammation though has received particular attention because of its widespread involvement in various neurological diseases and the potential for therapeutic modulation [75,102,103]. The major cellular mediators of this process are microglia.…”

Section: Discussionmentioning

confidence: 99%

Neurodegeneration and neuroinflammation are linked, but independent ofα-synuclein inclusions, in a seeding/spreading mouse model of Parkinson’s disease

Garcia

Jürgens-Wemheuer

Uriarte

et al. 2020

Preprint

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“…Triggered microglia respond early, before neurodegeneration is apparent, by producing neurotoxic compounds, and through what appears to be a series of different activation states as the disease progresses. Our findings contribute toward first answers to key unresolved questions around neuroinflammation in PD[100], and have important implications for the design of therapeutic interventions during the early stages of the disease.Additional files OHDA:6-Hydroxydopamine; 13 dpi: 13 days post injection; 90 dpi: 90 days post injection; A : amyloid beta peptide; AD: Alzheimer's disease; -syn: alpha-synuclein; BP: biological process; CD68: cluster of differentiation 68; Contra: contralateral; COX2: Cyclooxygenase 2; CNS: central nervous system; DA: dopamine; DAT: dopamine transporter; DEG: differentially expressed gene; ES; enrichment score; FDR: false discovery rate; GO: gene ontology; GSEA: gene set enrichment analysis; Iba1: ionized calcium binding adaptor molecule; Ipsi: ipsilateral; PBS: phosphate-buffered saline; PET assay: paraffinembedded tissue assay; PFF: Pre-formed fibril; Pfp: percent false positives; PLA: proximity ligation assay p-SER129--syn: alpha-synuclein phosphorylated at serine position 129; SN: Substantia Nigra; TDP43: TAR DNA-binding protein 43; TH: tyrosine-hydroxylase; TLR2: Toll-like receptor 2; WB: Western blot. Intrastriatal injection of murine -syn PFFs induced -syn inclusions in various brain regions.…”

mentioning

confidence: 71%

“…The relative contribution of these different processes to neuronal demise is unclear. Neuroinflammation though has received particular attention because of its widespread involvement in various neurological diseases and the potential for therapeutic modulation [73,100,101]. The major cellular mediators of this process are microglia.…”

Section: Discussionmentioning

confidence: 99%

Neurodegeneration and Neuroinflammation are Linked, but Independent of α-Synuclein Inclusions, in a Seeding/Spreading Mouse Model of Parkinson’s Disease

Garcia

Wemheuer

Uriarte

et al. 2020

Preprint

View full text Add to dashboard Cite

Abstract Background: Akey process of neurodegeneration in Parkinson’s disease (PD) is the transneuronal spreading of a-synuclein. Alpha-synuclein is a presynaptic protein that is implicated in the pathogenesis of PD and other synucleinopathies, where it forms, upon intracellular aggregation, pathological inclusions.Other hallmarks of PD include neurodegeneration and microgliosis in susceptible brain regions. Whether it is primarilytransneuronal spreading of a-synuclein particles,inclusion formation, or other mechanisms, such as inflammation,that cause neurodegeneration in PDis unclear.Methods: We used spreading/aggregation ofa-synuclein induced by intracerebral injection of a-synucleinpreformed fibrils into the mouse brain to address this question. We performed quantitative histological analysis for a-synuclein inclusions, neurodegeneration, and microgliosis in different brain regions, and a gene expression profiling of the ventral midbrain, at two different timepoints after disease induction.Results: We observed significant neurodegeneration and microgliosis in brain regions not only with,but alsowithouta-synuclein inclusions. We also observed prominent microgliosis in injured brain regions that did not correlate with neurodegeneration nor with inclusion load. In longitudinal gene expression profiling experiments, we observedearly and unique alterationslinkedto microglial mediated inflammation that preceded neurodegeneration, indicating an active role of microglia in inducing neurodegeneration. Our observations indicate that a-synuclein inclusion formation is not the major driverin the early phases of PD-like neurodegeneration, but that diffusible, oligomeric a-synuclein species,which induce unusual microglial reactivity, play a key role in this process.Conclusion: Our findings uncover new features of a-synuclein induced pathologies, in particular microgliosis, and point to the necessity of a broader view of the process of “prion-like spreading” of that protein.

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“…Several of the genes associated with PD risk function in the immune system 2 . Peripheral immune activation as well as neuroinflammation in the brain has been documented in idiopathic PD (iPD), 3 and these are thought to contribute to neuropathology and ultimately neurodegeneration.…”

Section: Figmentioning

confidence: 99%

Genetic and Environmental Factors in Parkinson's Disease Converge on Immune Function and Inflammation

et al. 2020

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A BS TRACT: Idiopathic Parkinson's disease (iPD) is a movement disorder characterized by the degeneration of dopaminergic neurons and aggregation of the protein α-synuclein. Patients with iPD vary in age of symptom onset, rate of progression, severity of motor and nonmotor symptoms, and extent of central and peripheral inflammation. Genetic and environmental factors are believed to act synergistically in iPD pathogenesis. We propose that environmental factors (pesticides and infections) increase the risk for iPD via the immune system and that the role of PD risk genes in immune cells is worthy of investigation. This review highlights the major PD-relevant genes expressed in immune cells and key environmental factors that activate immune cells and, alone or in combination with other factors, may contribute to iPD pathogenesis. By reviewing these interactions, we seek to enable the future development of immunomodulatory approaches to prevent or delay onset of iPD.

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Ten Unsolved Questions About Neuroinflammation in Parkinson's Disease

Cited by 158 publications

References 87 publications

Neurodegeneration and neuroinflammation are linked, but independent ofα-synuclein inclusions, in a seeding/spreading mouse model of Parkinson’s disease

Neurodegeneration and neuroinflammation are linked, but independent ofα-synuclein inclusions, in a seeding/spreading mouse model of Parkinson’s disease

Neurodegeneration and Neuroinflammation are Linked, but Independent of α-Synuclein Inclusions, in a Seeding/Spreading Mouse Model of Parkinson’s Disease

Genetic and Environmental Factors in Parkinson's Disease Converge on Immune Function and Inflammation

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