PIAS2-mediated blockade of IFN-[beta] signaling: a basis for sporadic Parkinson disease dementia

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 IFN[beta] or IFNAR1, the receptor for IFN...

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Published in:Molecular psychiatry 2021-10, Vol.26 (10), p.6083
Main Authors: Magalhaes, Joana, Tresse, Emilie, Ejlerskov, Patrick, Hu, Erling, Liu, Yawei, Marin, Andrea, Montalant, Alexia, Satriano, Letizia, Rundsten, Carsten Friis, Carlsen, Eva Maria Meier, Rydbirk, Rasmus, Sharifi-Zarchi, Ali, Andersen, Jesper Boje, Aznar, Susana, Brudek, Tomasz, Khodosevich, Konstantin, Prinz, Marco
Format: Article
Language:English
Subjects:
Brain research
Cellular signal transduction
Dementia
Development and progression
Genetic aspects
Health aspects
Interferon beta
Parkinson's disease
Protein kinases
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Summary: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 IFN[beta] or IFNAR1, the receptor for IFN[alpha]/[beta], causes pathological and behavioral changes resembling PDD, prompting us to hypothesize that dysregulated genes in IFN[beta]-IFNAR signaling pathway predispose one to sPD. By transcriptomic analysis, we found defective neuronal IFN[beta]-IFNAR signaling, including particularly elevated PIAS2 associated with sPDD. With meta-analysis of GWASs, we identified sequence variants in IFN[beta]-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 [alpha]-synuclein, in the brains of mice, which caused motor and cognitive impairments and correlated with intraneuronal phosphorylated (p)[alpha]-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.sup.-/- 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.
ISSN:1359-4184
1476-5578
DOI:10.1038/s41380-021-01207-w