Study first to link immunogenetics to non-familial Parkinson’s disease.


An estimated seven to ten million people worldwide are living with Parkinson’s disease (PD), which is an incurable and progressive disease of the nervous system affecting movement and cognitive function. More than half of PD patients develop progressive disease showing signs of dementia similar to Alzheimer’s disease.  Protein aggregates which eventually form larger Lewy bodies, are seen in PD, dementia with Lewy bodies, multiple system atrophy, and in some forms of Alzheimer’s disease; showing that neurodegenerative diseases associated with aging have disrupted neuronal homeostasis whose pathologies often overlap.

Neurodegenerative events in these diseases are linked to inflammation, however, despite this link, defects in genes regulating inflammation do not have an established causative role in neurodegeneration.  Now, a study from researchers team at University of Copenhagen shows that non-familial PD may be caused by functional changes in the immune regulating gene Interferon-beta (IFNβ). The team state that treatment with IFNβ-gene therapy successfully prevented neuronal death and disease effects in an experimental model of PD. The opensource study is published in the journal Cell.

Previous studies show that IFNβ belongs to the type I interferon family of cytokines and binding to its receptor, interferon-α/β receptor (IFNAR), results in immunoregulation including anti-viral and anti-inflammatory effects and benefits for multiple sclerosis patients. However, the role of IFNβ in classic neurodegenerative diseases is unknown. The current study shows that deletion of IFNβ is sufficient to cause a cascade of neurodegenerative events.

The current study used IFNβ knockout mice with spontaneous pathologies mimicking major aspects of human neurodegeneration such as PD and DLB to show that the immune gene IFNβ plays a vital role in keeping neurons healthy.  Data findings show that IFNβ is essential for neurons to recycle waste proteins. The researchers explain that without this recycling system, the waste proteins accumulate in the disease-associated structures, Lewy bodies, and with time the neurons die.  The team observed that mice missing IFNβ, developed Lewy bodies in parts of the brain which control body movement and restoration of memory, and as a result developed pathology similar to patients with PD and dementia with Lewy bodies. 

The group state that 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. They go on to add that it is independent of gene mutations known from familial PD and when an IFNβ-gene therapy was introduced neuronal death and disease development was prevented.  The lab conclude that while hereditary gene mutations have long been known to play a role in familial PD, their findings offer one of the first models for non-familial PD, which comprises the majority (90-95%) of patients suffering from PD.

The team surmise that current treatments are effective at improving the early motor symptoms of the disease, however, as the disease progress, the treatment effect is lost.  They go on to add that they hope is that their findings will enable development of more effective treatment of PD.  For the future, the researchers plan to gain a better understanding of the molecular mechanisms by which IFNβ protects neurons and thereby prevents movement disorders and dementia.

Source: University of Copenhagen

 

Neurodegenerative diseases have been linked to inflammation, but whether altered immunomodulation plays a causative role in neurodegeneration is not clear. We show that lack of cytokine interferon-β (IFN-β) signaling causes spontaneous neurodegeneration in the absence of neurodegenerative disease-causing mutant proteins. Mice lacking Ifnb function exhibited motor and cognitive learning impairments with accompanying α-synuclein-containing Lewy bodies in the brain, as well as a reduction in dopaminergic neurons and defective dopamine signaling in the nigrostriatal region. Lack of IFN-β signaling caused defects in neuronal autophagy prior to α-synucleinopathy, which was associated with accumulation of senescent mitochondria. Recombinant IFN-β promoted neurite growth and branching, autophagy flux, and α-synuclein degradation in neurons. In addition, lentiviral IFN-β overexpression prevented dopaminergic neuron loss in a familial Parkinson’s disease model. These results indicate a protective role for IFN-β in neuronal homeostasis and validate Ifnb mutant mice as a model for sporadic Lewy body and Parkinson’s disease dementia.  Lack of Neuronal IFN-β-IFNAR Causes Lewy Body- and Parkinson’s Disease-like Dementia.  Ejlerskov et al 2015.

Neurodegenerative diseases have been linked to inflammation, but whether altered immunomodulation plays a causative role in neurodegeneration is not clear. We show that lack of cytokine interferon-β (IFN-β) signaling causes spontaneous neurodegeneration in the absence of neurodegenerative disease-causing mutant proteins. Mice lacking Ifnb function exhibited motor and cognitive learning impairments with accompanying α-synuclein-containing Lewy bodies in the brain, as well as a reduction in dopaminergic neurons and defective dopamine signaling in the nigrostriatal region. Lack of IFN-β signaling caused defects in neuronal autophagy prior to α-synucleinopathy, which was associated with accumulation of senescent mitochondria. Recombinant IFN-β promoted neurite growth and branching, autophagy flux, and α-synuclein degradation in neurons. In addition, lentiviral IFN-β overexpression prevented dopaminergic neuron loss in a familial Parkinson’s disease model. These results indicate a protective role for IFN-β in neuronal homeostasis and validate Ifnb mutant mice as a model for sporadic Lewy body and Parkinson’s disease dementia. Lack of Neuronal IFN-β-IFNAR Causes Lewy Body- and Parkinson’s Disease-like Dementia. Ejlerskov et al 2015.

 

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