Brain inflammation burgeons during many neurodegenerative diseases, but it remains unclear exactly how this process contributes to pathology. In the October 8 Cell, researchers led by Shohreh Issazadeh-Navikas at the University of Copenhagen, Denmark, report evidence that inflammatory dysfunction alone can precipitate neurodegeneration. The authors analyzed mice that lacked the anti-inflammatory cytokine interferon β (IFN-β). The animals developed widespread pathology that shared features with Parkinson’s disease and dementia with Lewy bodies, including the accumulation of α-synuclein. The authors traced this buildup to a breakdown in the cellular waste disposal process known as autophagy. The findings suggest a crucial role for IFN-β in maintaining neuronal homeostasis, Issazadeh-Navikas said.
IFN- β has not been tied to neuron maintenance previously. Even so, this anti-inflammatory protein has been used for decades to treat people with multiple sclerosis (MS), and it is known to affect transcription of numerous genes (see Der et al., 1998). In MS, IFN- β dampens T cell responses, keeping these immune cells from attacking the myelin that insulates neurons (see Yong et al., 1998). Previously, Issazadeh-Navikas and colleagues reported that knocking out IFN- β in mice with experimental autoimmune encephalomyelitis, a model of MS, worsened neuroinflammation (see Teige et al., 2003). This led the authors to wonder how IFN- β affects normal brain function, and whether it might play a role in neurodegenerative disease.
To investigate, first author Patrick Ejlerskov characterized IFN-β knockout mice (see Erlandsson et al., 1998). He found widespread neurodegeneration and discovered that it worsened with age. Starting at 1.5 months old, neurons withered at an accelerated rate in the hippocampus and olfactory bulb. By 6 and 12 months, respectively, death spread to the cerebellum and striatum. Knockouts generated fewer new neurons than wild-type, and their neurons had shorter, simpler processes. These brain changes were accompanied by behavioral deficits. From 3 months on, the knockouts struggled more than wild-types to balance on a spinning rod and cling to a wire. They reacted more strongly to pain, and had poorer spatial memory in water-maze tests.
To glean clues to what underlay these defects, the authors analyzed gene expression in knockout neurons using microarrays. They saw a boost in cell death pathways, as well as in genes linked to Parkinson’s, Huntington’s, and Alzheimer’s disease. In addition, many genes involved in autophagy were altered. The microarray data fit most closely with a Parkinson’s profile.
Experiments on cultured cortical and granular neurons from the IFN-β knockouts confirmed the microarray findings. In the normal autophagic process, autophagosomes containing waste proteins fuse with lysosomes, which digest the trash. Knockout neurons, however, possessed excess autophagosomes and very few autolysosomes, suggesting a block in the maturation of the latter (see image above). Knockout neurons also accumulated numerous aged, senescent mitochondria, implying a failure to dispose of these organelles as well.
Weak autophagy can cause many proteins to accumulate. The authors measured a build-up of phosphorylated α-synuclein, phospho-tau, and ubiquinated proteins. Because the gene-expression data hinted at a Parkinson’s phenotype, the authors examined the dopaminergic system in knockout mice. The animals lost dopaminergic neurons and accumulated α-synuclein deposits in Lewy bodies from 3 months on. Similar effects on autophagy and α-synuclein occurred in mice lacking the IFN-β receptor, IFNAR, strengthening the idea that the defects arose through this signaling pathway.
“The link between IFN-β and autophagy is one of the most interesting findings here,” said Mark Cookson at the National Institutes of Health, Bethesda, Maryland. He suggested that future studies investigate how IFN-β affects autophagy, and whether the mechanism is specific to IFN-β or occurs with knockout of other cytokines as well.
Neurons dispose of most of their α-synuclein through autophagy, so this protein is particularly prone to build up when autophagy slows down, Cookson added. Several genes associated with Parkinson’s, such as LRRK2, have been implicated in autophagy (see Jun 2012 news; Feb 2014 news).
Notably, degeneration in the IFN-β knockouts occurs without any mutation in known neurodegenerative proteins. “I think this opens a new window for looking at sporadic neurodegenerative diseases, and why they have associations with neuroinflammation,” Issazadeh-Navikas said. She wondered if perturbations in IFN-β signaling might contribute to the development of Parkinson’s, and plans to look for correlations between PD and genetic variants in IFN-β and related proteins.
If IFN-β speeds digestion of α-synuclein, could it help Parkinson’s patients? Some evidence from mice supports this idea. The authors injected lentivirus expressing the cytokine into the substantia nigra of rats that overexpress human α-synuclein (see Decressac et al., 2013). The treatment pumped up autophagy, preserved dopaminergic neurons, and improved motor control. However, delivery of the cytokine might pose problems for treating PD because it stays outside the blood-brain barrier. In MS treatment, IFN-β is given systemically and does not need to enter the brain. To promote autophagy, the cytokine needs to act directly on neurons.—Madolyn Bowman Rogers
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