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Model in mice by University of Copenhagen scientists reveals routes leading to Parkinsons and its eventual progression to dementia
As far as current wisdom about Parkinsons Disease goes – well – we only understand about 5 per cent of the problem. But a University of Copenhagen research team may now have unearthed a small part of the remaining 95 per cent: What causes the disease beyond genetic mutations; and what factors decide if and when a patient suffers from dementia?
Researcher Patrick Ejlerskov and colleagues based at the Biotech Research and Innovation Centre (BRIC) at the University of Copenhagen (UCPH) have identified a new role for a key member of our immune system in fighting dementia in Parkinson’s disease. The team is led by Professor Shohreh Issazadeh-Navikas and the research has been published in the prestigious scientific journal Cell.
Parkinsons Disease (PD) occurs late in life with major symptoms including shivers, loss of movement, frozen limbs. Most patients will also develop dementia as the disease progresses.
Patients accumulate a protein called ‘alpha-synuclein’ in the brain that forms large protein clumps called ‘Lewy bodies’ – something that is considered a hallmark of the disease. An estimated 7 to 10 million people worldwide are living with Parkinson’s disease – and it comes second only to Alzheimer’s in dementia-associated diseases. Both diseases have a big impact on the quality of life in patients requiring long term personal care as well as an economic impact on the healthcare system.
Nerve cell communication: The left panel shows a healthy neuron – interferon beta helps the neighbouring nerve cells find each other and ‘hold hands’. Right panel shows how in nerve cells lacking interferon beta – they lose their hands and cannot find each other. They start forming Lewy body clumps (black doughnut) eventually causing Parkinsons disease with dementia. (Picture source: Cell.com Volume 163, Issue 2, 8 October 2015, Pages 324–339)
Interferons are a kind of secreted molecule called ‘cytokines’ which are released by the body in response to viruses, bacteria, fungi and tumor cells. Patrick Ejlerskov recalls how the discovery came about by chance:
“We were originally looking at understanding the basic role of interferon-beta [a member of the interferon family, ed.] in multiple sclerosis. Supplementing those patients with interferon-beta is already approved as treatment. While studying mice lacking the interferon-beta gene, we observed that they had strong behavioural defects very similar to Parkinson’s Disease. So we examined the brain of these mice, and we found the same kind of protein clumps as seen in patients with Parkinson’s. So we were naturally quite excited!”
The scientists failed several times trying to establish neuron cultures from these mice leading the team to doubt their method.
But eventually they understood that neurons from these mice were unable to form normal nerve structures in a dish. Upon supplying interferon beta externally we were able to understand which pathways were different in the diseased and treated neurons. Basically, the protein recycling (similar to garbage recycling) process of the nerve cells were affected.
“We could conclude that besides its role in immune defence, interferon beta also has a role in the waste management of proteins in the brain. Without this garbage management the mice develop neurodegenerative disease similar to Parkinson’s disease by forming protein clumps eventually giving rise to dementia.
Our claim was further strengthened by the fact that genetically modified mice lacking interferon beta receptor [the partner gene of interferon-beta, ed,] showed similar defects in the brain”.
At present, 5 – 10 per cent of all Parkinson’s disease patients can be explained by inherited gene mutations. In the remaining non-familial cases the initiating factors are unknown.
Patrick believes that the new link of interferon-beta in Parkinson’s disease can drive new efforts to test if a loss of interferon-beta signaling can explain what we observe in the majority of patients.
“This is something we currently analyze through a collaboration with Bispebjerg hospital,” adding that “the next step is to see if these data can be recapitulated in samples from human patients. Based on this we can evaluate if targeting interferon-beta signaling therapeutically could benefit people with Parkinson’s disease and dementia”.
Professor Shohreh Issazadeh Navikas of UCPH is leading the team.
“This is one of the first genes found to cause pathology and clinical features of non-familial Parkinson’s disease and the previously unexplained dementia associated Lewy bodies (DLB), through the accumulation of disease-causing proteins. It is independent of gene mutations known from familial Parkinson’s disease and when we introduced interferon-beta–gene therapy, we could prevent neuronal death and disease development.”
“Our hope is that this knowledge will enable development of more effective treatment,” she says.
A link to the research paper in Cell can be found here.
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