Mitochondrial function is clearly important in the development of Parkinson’s disease. The mutations associated with increased risk of Parkinson’s are related to mitochondrial quality control and function. Greater mitochondrial dysfunction makes the dopaminergic neurons most vulnerable to Parkinson’s pathology that much more vulnerable, though it is an open question as to whether this is more a matter of disrupted energy metabolism or increased inflammatory signaling, both of which result from the presence of failing mitochondria in cells. Here, researchers report that expression of IFNAR1 is reduced in Parkinson’s disease. That reduced IFNAR1 expression causes mitochondrial dysfunction via impairment of the quality control mechanisms of mitophagy, the same sort of issue as accelerates Parkinson’s in genetic cases. Establishing whether or not this discovery may lead to a viable therapy to delay onset and progression of Parkinson’s disease via increased IFNAR1 expression will require further research and development.
Dysregulated interferon-alpha/beta-receptor 1 (IFNAR1) signaling was recently identified to contribute to the development of sporadic Parkinson’s disease (PD) into PD with Dementia (PDD). The molecular, cellular, and phenotypic impacts of brain IFNAR1 loss in aging have not been explored in vivo, which may reveal novel disease mechanisms and therapeutic targets. Baseline IFNAR1 expression varies among major brain cell types, including neurons and astrocytes, and is differentially affected in PD and Lewy Body Dementia patients compared to unaffected controls.
Neuron- and astrocyte-specific transcriptomic and proteomic alterations in IFNAR1 knockout mice implicate mitochondrial defects, defective mitophagy, and synergistic dysfunctional neurotransmission upon IFNAR1 loss, leading to glucose hypermetabolism measured by functional metabolic analysis. Consequently, IFNAR1 knockout mice exhibited PDD-like pathogenesis, including dopaminergic cell loss in the substantia nigra, cortical neurodegeneration, Lewy-body-like inclusions, neuroinflammation, and progressive PDD-like behavior deficits. Brain cell-specific IFNAR1 loss examined in vivo revealed delayed but distinct development of PDD-like phenotypes, where neuropathology, motor, and cognitive behavior deficits were recapitulated only in mice lacking neuronal IFNAR1, and behavior resembling neuropsychiatric abnormalities recapitulated only in mice lacking astrocytic IFNAR1.
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