PIAS2-mediated blockade of IFN-β signaling:a basis for sporadic Parkinson disease dementia
| Autor: | Alexia Montalant, Thomas Gasser, Marco Prinz, Patrick Ejlerskov, Joana Magalhaes, Erling Hu, Shohreh Issazadeh-Navikas, Emilie Tresse, Susana Aznar, Ali Sharifi-Zarchi, Yawei Liu, Carsten Friis Rundsten, Tomasz Brudek, Jesper B. Andersen, Eva Maria Meier Carlsen, Manu Sharma, Jean-François Perrier, Rasmus Rydbirk, Letizia Satriano, Konstantin Khodosevich, Andrea Marin |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Neurite Diseases medicine.disease_cause Article Mice 03 medical and health sciences Cellular and Molecular Neuroscience 0302 clinical medicine Mitophagy mental disorders medicine Animals Humans Dementia Molecular Biology Mice Knockout Gene knockdown business.industry Dopaminergic Neurons Parkinson Disease Interferon-beta medicine.disease Protein Inhibitors of Activated STAT Psychiatry and Mental health 030104 developmental biology Nerve Degeneration alpha-Synuclein Cancer research Phosphorylation Ectopic expression Signal transduction business 030217 neurology & neurosurgery Oxidative stress Signal Transduction Neuroscience |
| Zdroj: | Magalhaes, J, Tresse, E, Ejlerskov, P, Hu, E, Liu, Y, Marin, A, Montalant, A, Satriano, L, Rundsten, C F, Carlsen, E M M, Rydbirk, R, Sharifi-Zarchi, A, Andersen, J B, Aznar, S, Brudek, T, Khodosevich, K, Prinz, M, Perrier, J F M, Sharma, M, Gasser, T & Issazadeh-Navikas, S 2021, ' PIAS2-mediated blockade of IFN-β signaling : a basis for sporadic Parkinson disease dementia ', Molecular Psychiatry, vol. 26, pp. 6083–6099 . https://doi.org/10.1038/s41380-021-01207-w Molecular Psychiatry |
| DOI: | 10.1038/s41380-021-01207-w |
| Popis: | Familial Parkinson disease (PD) is associated with rare genetic mutations, but the etiology in most patients with sporadic (s)PD is largely unknown, and the basis for its progression to dementia (sPDD) is poorly characterized. We have identified that loss of IFNβ or IFNAR1, the receptor for IFNα/β, causes pathological and behavioral changes resembling PDD, prompting us to hypothesize that dysregulated genes in IFNβ-IFNAR signaling pathway predispose one to sPD. By transcriptomic analysis, we found defective neuronal IFNβ-IFNAR signaling, including particularly elevated PIAS2 associated with sPDD. With meta-analysis of GWASs, we identified sequence variants in IFNβ-IFNAR-related genes in sPD patients. Furthermore, sPDD patients expressed higher levels of PIAS2 mRNA and protein in neurons. To determine its function in brain, we overexpressed PIAS2 under a neuronal promoter, alone or with human α-synuclein, in the brains of mice, which caused motor and cognitive impairments and correlated with intraneuronal phosphorylated (p)α-synuclein accumulation and dopaminergic neuron loss. Ectopic expression of neuronal PIAS2 blocked mitophagy, increased the accumulation of senescent mitochondrial and oxidative stress, as evidenced by excessive oxDJ1 and 8OHdG, by inactivating ERK1/2-P53 signaling. Conversely, PIAS2 knockdown rescued the clinicopathological manifestations of PDD in Ifnb–/– mice on restoring mitochondrial homeostasis, oxidative stress, and pERK1/2-pP53 signaling. The regulation of JAK-STAT2-PIAS2 signaling was crucial for neurite outgrowth and neuronal survival and excitability and thus might prevent cognitive impairments. Our findings provide insights into the progression of sPD and dementia and have implications for new therapeutic approaches. |
| Databáze: | OpenAIRE |
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