Parkinson and Lewy Body-like Dementia Triggers

Danish and German scientists have identified impaired cytokine interferon-β (IFN-β) signaling as a possible molecular trigger for Parkinson disease dementia, as well as the related neurodegenerative disorder, Lewy body dementia. Correcting deficits in IFN-β via gene therapy may one day provide a treatment for these neurodegenerative diseases.

Parkinson disease is characterized by tremor and rigidity, caused by loss of basal ganglia dopaminergic neurons and marked by the presence of Lewy bodies-aggregated protein deposits containing alpha-synuclein. Dementia is another characteristic of later stages of the disease. Lewy body dementia shares overlapping characteristics with Parkinson disease. The two disorders are more distinct in earlier stages, since Parkinson is characterized by movement symptoms initially, while dementia occurs earlier in Lewy body disease.

The research report appeared in the prestigious journal Cell. According to the study, IFN-β is responsible for neuronal homeostasis and cellular clean-up, and the absence of the cytokine could trigger neurodegenerative disease.

Led by Patrick Ejlerskov of the University of Copenhagen, the researchers studied mice that lacked IFN- β, known as ifnb mutant mice. The animals had impairments in both cognitive function and in movement, as measured by a water maze and RotaRod test, both standard behavioral tasks. The scientists used immunostaining of the mouse brain to identify the presence of Lewy bodies in the brain containing the characteristic protein alpha-synuclein. Surprisingly, they also found a reduction in dopamine neurons in the substantia nigra as well as impaired dopamine neuronal signaling-hallmark signs of Parkinson disease.

According to the study authors, the alpha-synuclein and Lewy body accumulation are the consequence of “late-stage autophagy.” Autophagy is a mechanism for cleaning up the cell. The process degrades proteins, organelles, lipids, and aggregates of protein and is a critical homeostatic process for the neuron.

“We found that IFN-β is essential for neurons’ ability to recycle waste proteins. Without this, the waste proteins accumulate in disease-associated structures called Lewy bodies and with time the neurons die,” noted Ejlerskov in a press release.

As a final stage of the study, the scientists tested the effects of corrective gene therapy in a rat model of Parkinson disease induced by injecting human alpha-synuclein into the rat substantia nigra. They used a lentivirus to over-express IFN-β in one group of the Parkinsonian  rats while another control group received the lentivirus only, as a sham treatment. The animals without the corrective gene therapy developed problems with autophagy and accumulation of several proteins in the brain, including alpha-synuclein. The animals with IFN-β overexpression did not have these problems. The gene therapy also protected dopamine neurons in the substantia nigra and improved movement problems in the animals. The scientists concluded in their manuscript “We showed that Ifnb gene therapy reversed pathology in a familial PD model, by promoting autophagy and a-syn clearance, which preserved DA neurons and associated neurologic deficit.”

Not only did this research study identify a possible new animal model for Parkinson disease and Lewy body dementia, but it the results also suggest a potential new avenue for gene therapy in these neurological conditions.

In a press release, principal investgator Shohreh Issazadeh-Navikas remarked, “This is one of the first genes found to cause pathology and clinical features of non-familial PD and DLB, through accumulation of disease-causing proteins. It is independent of gene mutations known from familial PD and when we introduced IFNβ-gene therapy, we could prevent neuronal death and disease development. Our hope is that this knowledge will enable development of more effective treatment of PD.”

Reference: Ejlerskov P, et al. Lack of neuronal IFN-β-IFNAR causes Lewy body- and Parkinson’s disease-like dementia. Cell. 2015;163(2):324-339.