Interferon-γ induces progressive nigrostriatal degeneration and basal ganglia calcification

Abstract

We report that CNS directed expression of Interferon (IFN) -γ results in basal ganglia calcification, reminiscent of human idiopathic basal ganglia calcification (IBGC), and nigrostriatal degeneration. Our results show that IFN-γ mediates age-progressive nigrostriatal degeneration in the absence of exogenous stressors. Further study of this model may provide unique insight into selective nigrostriatal degeneration in human IBGC and other Parkinson syndromes.

Reciprocal Negative Cross-Talk between Liver X Receptors (LXRs) and STAT1: Effects on IFN-γ–Induced Inflammatory Responses and LXR-Dependent Gene Expression

“…Recent studies place IFN-g as a prime factor in inflammation-induced neurodegeneration (32)(33)(34). In correlation with this suggestion, we show that intraventricular injection with IFN-g results in upregulation of the expression of several chemokines and that pretreatment with the LXR agonist T1317 inhibits their induction.…”

“…3A). Production of IFN-g contributes to the initiation and amplification of local immune responses, potentially leading to neurodegeneration in the CNS (32)(33)(34). We used a murine model of acute response to IFN-g based on injection of this cytokine in the ventricular region of the brain.…”

Leucine-rich Repeat Kinase 2 (LRRK2) Pharmacological Inhibition Abates α-Synuclein Gene-induced Neurodegeneration

“…␣-Synuclein neurodegeneration can be blocked by modulation of neuroinflammatory processes through genetic knockout of MHC-II and Fc or through administration of the immunophilin ligand FK506 (30 -32). Dopaminergic neurons in the SNpc appear to be particularly sensitive to proinflammatory cytokines, suggesting that the model used here is, at least in part, dependent on proinflammatory responses to kill dopaminergic neurons (33,34). LRRK2 KO rodents show reduced proinflammatory responses in the brain in response to lipopolysaccharide or HIV-trans-activating protein administration (16,35).…”

Inhibition of the JAK/STAT Pathway Protects Against α-Synuclein-Induced Neuroinflammation and Dopaminergic Neurodegeneration

“…IFN-␥ has been implicated in contributing to degeneration of DA neurons through a mechanism involving microglia, and IFN-␥-deficient mice are protected against MPTP-induced neurotoxicity (Mount et al, 2007). Conversely, overexpression of IFN-␥ in mice promoted microgliosis and nigrostrial degeneration (Chakrabarty et al, 2011). Microglia produce IFN-␥ in response to ␣-SYN (Cebrián et al, 2014), and Th1 cells produce IFN-␥ in the MPTP model (Olson et al, 2015).…”