PIAS2-mediated blockade of IFN-β signaling: a basis for sporadic Parkinson disease dementia

Magalhaes, Joana; Tresse, Emilie; Ejlerskov, Patrick; Hu, Erling; Liu, Yawei; Marín, Andrea; Montalant, Alexia; Satriano, Letizia; Rundsten, Carsten Friis; Carlsen, Eva Maria Meier; Rydbirk, Rasmus; Sharifi‐Zarchi, Ali; Andersen, Jesper B.; Aznar, Susana; Brudek, Tomasz; Khodosevich, Konstantin; Prinz, Marco; Perrier, Jean-François Marie; Sharma, Manu; Gasser, Thomas; Issazadeh‐Navikas, Shohreh

doi:10.1038/s41380-021-01207-w

Cited by 46 publications

(47 citation statements)

References 77 publications

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“…Moreover, patient microglia presented a diseasespecific gene expression signature, indicating a significant role of these cells in the pathogenesis of the movement disorder (Smajić et al, 2020). Also, most recently, genes of the IFN-γ signaling pathway were found to be dysregulated in IPD patients (Magalhaes et al, 2021).…”

Section: Introductionmentioning

confidence: 97%

iPSC-Derived Microglia as a Model to Study Inflammation in Idiopathic Parkinson’s Disease

Badanjak

Mulica

Smajić

et al. 2021

Front. Cell Dev. Biol.

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Parkinson’s disease (PD) is a neurodegenerative disease with unknown cause in the majority of patients, who are therefore considered “idiopathic” (IPD). PD predominantly affects dopaminergic neurons in the substantia nigra pars compacta (SNpc), yet the pathology is not limited to this cell type. Advancing age is considered the main risk factor for the development of IPD and greatly influences the function of microglia, the immune cells of the brain. With increasing age, microglia become dysfunctional and release pro-inflammatory factors into the extracellular space, which promote neuronal cell death. Accordingly, neuroinflammation has also been described as a feature of PD. So far, studies exploring inflammatory pathways in IPD patient samples have primarily focused on blood-derived immune cells or brain sections, but rarely investigated patient microglia in vitro. Accordingly, we decided to explore the contribution of microglia to IPD in a comparative manner using, both, iPSC-derived cultures and postmortem tissue. Our meta-analysis of published RNAseq datasets indicated an upregulation of IL10 and IL1B in nigral tissue from IPD patients. We observed increased expression levels of these cytokines in microglia compared to neurons using our single-cell midbrain atlas. Moreover, IL10 and IL1B were upregulated in IPD compared to control microglia. Next, to validate these findings in vitro, we generated IPD patient microglia from iPSCs using an established differentiation protocol. IPD microglia were more readily primed as indicated by elevated IL1B and IL10 gene expression and higher mRNA and protein levels of NLRP3 after LPS treatment. In addition, IPD microglia had higher phagocytic capacity under basal conditions—a phenotype that was further exacerbated upon stimulation with LPS, suggesting an aberrant microglial function. Our results demonstrate the significance of microglia as the key player in the neuroinflammation process in IPD. While our study highlights the importance of microglia-mediated inflammatory signaling in IPD, further investigations will be needed to explore particular disease mechanisms in these cells.

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Section: Introductionmentioning

confidence: 97%

iPSC-Derived Microglia as a Model to Study Inflammation in Idiopathic Parkinson’s Disease

Badanjak

Mulica

Smajić

et al. 2021

Front. Cell Dev. Biol.

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“…For neuronal cultures, 2-3 pups were required to culture an appropriate number of neurons per biological replicate for several simultaneous conditions and use for immunofluorescence, western blot, and qPCR analyses. To abide by 3R ethical principles (https://en.3rcenter.dk/3r), we evaluated the minimal number of biological replicates (n = 3-6) required to replicate our findings in Wt versus Ifnb À/À neurons both in this study and from previous work, [21][22][23] meanwhile concurrently evaluating the same differences in DKO and Snca À/À neurons.…”

Section: Statistical Analysis and Sample Size Determinationmentioning

confidence: 99%

“…Defective neuronal signaling with the CNS immunomodulatory cytokine interferon beta (IFN-β) causes chronic neuroinflammation, 20,21 dysfunction of which is associated with sporadic PDD. 22 IFN-β knockout (Ifnb À/À ) mice develop aging-related motor and cognitive deficits, nigrostriatal dopaminergic neurodegeneration, and spontaneous development of α-syn + LB-like inclusions in the brain . 23,24 Here, the Ifnb À/À mouse is used as a PDD model to investigate the in vivo impact of endogenous α-syn removal on development of PDD-like behavior and pathology by generating IFN-β/α-syn double-knockout (DKO) mice.…”

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confidence: 99%

Neuronal TNFα, Not α‐Syn, Underlies PDD‐Like Disease Progression in IFNβ‐KO Mice

Villanueva

Tresse

Liu

et al. 2021

Annals of Neurology

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Objective: Parkinson's disease (PD) manifests in motor dysfunction, non-motor symptoms, and eventual dementia (PDD). Neuropathological hallmarks include nigrostriatal neurodegeneration, Lewy body (LB) pathology, and neuroinflammation. Alpha-synuclein (α-syn), a primary component of LBs, is implicated in PD pathogenesis, accumulating, and aggregating in both familial and sporadic PD. However, as α-syn pathology is often comorbid with amyloid-beta (Aβ) plaques and phosphorylated tau (pTau) tangles in PDD, it is still unclear whether α-syn is the primary cause of neurodegeneration in sporadic PDD. We aimed to determine how the absence of α-syn would affect PDD manifestation. Methods: IFN-β knockout (Ifnb À/À ) mice spontaneously develop progressive behavior abnormalities and neuropathology resembling PDD, notably with α-syn + LBs. We generated Ifnb/Snca double knockout (DKO) mice and evaluated their behavior and neuropathology compared with wild-type (Wt), Ifnb À/À , and Snca À/À mice using immunohistochemistry, electron microscopy, immunoblots, qPCR, and modification of neuronal signaling. Results: Ifnb/Snca DKO mice developed all clinical PDD-like behavioral manifestations induced by IFN-β loss. Independently of α-syn expression, lack of IFN-β alone induced Aβ plaques, pTau tangles, and LB-like Aβ + /pTau + inclusion bodies and neuroinflammation. IFN-β loss caused significant elevated glial and neuronal TNF-α and neuronal TNFR1, associated with neurodegeneration. Restoring neuronal IFN-β signaling or blocking TNFR1 rescued caspase 3/t-BIDmediated neuronal-death through upregulation of c-FLIP S and lowered intraneuronal Aβ and pTau accumulation. Interpretation: These findings increase our understanding of PD pathology and suggest that targeting α-syn alone is not sufficient to mitigate disease. Targeting specific aspects of neuroinflammation, such as aberrant neuronal TNF-α/TNFR1 or IFN-β/IFNAR signaling, may attenuate disease.

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“…A growing body of evidence is indicating that viruses that cause parkinsonism are also associated with idiopathic Parkinson’s Disease (PD) [ 35 , 38 ]. PD is lifelong, characterized by neuronal death, and has about a 15-year life expectancy after the onset of symptoms [ 33 ].…”

Section: Introductionmentioning

confidence: 99%

“…Viral parkinsonism is theorized to be a result of immune mediated complications resulting in neuroinflammation even though in many cases, CT and MRI are normal [ 24 , 43 ]. Recent work has shown that blockage of the IFN1 pathway causes mitochondrial dysfunction in the brain which causes neuronal death [ 38 ]. Many viruses, including DENV, block IFN1 in order to evade the immune system and establish infection [ 44 , 45 ].…”

Section: Introductionmentioning

confidence: 99%

Viral Parkinsonism: An underdiagnosed neurological complication of Dengue virus infection

2022

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Dengue virus (DENV) is a flavivirus that is a significant cause of human disease costing billions of dollars per year in medical and mosquito control costs. It is estimated that up to 20% of DENV infections affect the brain. Incidence of DENV infections is increasing, which suggests more people are at risk of developing neurological complications. The most common neurological manifestations of DENV are encephalitis and encephalopathy, and movement disorders such as parkinsonism have been observed. Parkinsonism describes syndromes similar to Parkinson’s Disease where tremors, stiffness, and slow movements are observed. Parkinsonism caused by viral infection is characterized by patients exhibiting at least two of the following symptoms: tremor, bradykinesia, rigidity, and postural instability. To investigate DENV-associated parkinsonism, case studies and reports of DENV-associated parkinsonism were obtained from peer-reviewed manuscripts and gray literature. Seven reports of clinically diagnosed DENV-associated parkinsonism and 15 cases of DENV encephalitis, where the patient met the case criteria for a diagnosis of viral parkinsonism were found. Clinically diagnosed DENV-associated parkinsonism patients were more likely to be male and exhibit expressionless face, speech problems, and lymphocytosis. Suspected patients were more likely to exhibit tremor, have thrombocytopenia and low hemoglobin. Viral parkinsonism can cause a permanent reduction in neurons with consequential cognitive and behavior changes, or it can leave a latent imprint in the brain that can cause neurological dysfunction decades after recovery. DENV-associated parkinsonism is underdiagnosed and better adherence to the case definition of viral parkinsonism is needed for proper management of potential sequalae especially if the patient has an ongoing or potential to develop a neurodegenerative disease.

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PIAS2-mediated blockade of IFN-β signaling: a basis for sporadic Parkinson disease dementia

Cited by 46 publications

References 77 publications

iPSC-Derived Microglia as a Model to Study Inflammation in Idiopathic Parkinson’s Disease

iPSC-Derived Microglia as a Model to Study Inflammation in Idiopathic Parkinson’s Disease

Neuronal TNFα, Not α‐Syn, Underlies PDD‐Like Disease Progression in IFNβ‐KO Mice

Viral Parkinsonism: An underdiagnosed neurological complication of Dengue virus infection

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