Abstract
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.
Highlights
The etiology of sporadic Parkinson disease is unknown, which complicates its treatment
To determine the relevance of defective neuronal IFNβ-IFNAR signaling to PD, we generated a common type I IFN gene signature, based on the RESULTS Neuronal IFNβ–IFNAR signaling is defective and associated with increased PIAS2 in patients with sporadic Parkinson disease dementia by transcriptomic analysis rare familial genes that are associated with PD have been identified, the genes that have been linked to the etiology of sPD remain poorly characterized
PIAS2 knockdown reverses Parkinson disease dementia (PDD) pathology by preventing mitochondrial oxidative stress and restoring pERK1/2pP53 signaling we examined whether siRNA-mediated knockdown of Pias2 in the brain of Ifnb–/– mice mitigates the signals that contribute to mitochondrial pathology. siRNA knockdown of PIAS2 (siPIAS2) enhanced ERK1/2 activation— pERK1/2 increased and translocated primarily to the nucleus, and the pERK/ERK ratio rose significantly (Fig. 6a, b)
Summary
The etiology of sporadic Parkinson disease (sPD) is unknown, which complicates its treatment. All PD patients experience motor dysfunction due to loss of dopaminergic neurons in the substantia nigra (SN), correlating with pathogenic α-synuclein (α-syn) aggregates and Lewy bodies [1]. These aggregates amass in an increasingly larger area of the brain as PD progresses and causes such secondary symptoms as dementia [1, 2]. Familial forms only constitute approximately 5% of all PD cases [5, 6]—the origin of the remaining sporadic cases remains unknown
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