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Pathway blockage found to be major cause of Parkinson’s Disease

The mitochondria in the cells of the brain are damaged by an obstruction on a key pathway, the type 1 interferon-pathway. This causes neurons to die slowly, which causes Parkinson’s Disease symptoms. It is also why it often leads to dementia and Alzheimer’s disease.

Parkinson’s disease (PD) affects 7 to 10 million people globally. The illness is the second most prevalent neurodegenerative disorder of aging and the most prominent mobility disorder, although the etiology is unclear.

A team of researchers from the University of Copenhagen have discovered that sporadic Parkinson’s Disease, which accounts for 90 to 95 percent of all Parkinson’s Disease cases, is caused by a disruption of a pathway that governs the nerve cell’s powerhouse, the mitochondria.

“Just like when people eat, cells take what they need and get rid of the rest waste products. But if our brain cells have this specific kind of signaling blockage, it means that the powerhouse of the cell – mitochondria – cannot get cleaned up after being damaged,” explains corresponding author and group leader Professor Shohreh Issazadeh-Navikas at the Biotech Research & Innovation Centre.

Because of the obstruction, a large number of damaged mitochondria accumulate, and the cells are unable to create adequate energy. It causes neurons to die slowly, which causes the development of Parkinson’s Disease symptoms, and why it often leads to dementia.

The obstruction is produced by an imbalance of immune genes, primarily a pathway known as type 1 interferon, which is typically responsible for fighting viruses but has recently been shown to also regulate nerve cell energy supply.

‘Every part of our body needs to be regulated. We get a signal to stop eating, when we are full, and the same thing happens everywhere else in our body. If we get an infection, parts of our body need to fight it and stop it from replicating. But when the infection is cleaned up, the signal should subside. This is the job of a protein called PIAS2. That causes the blockage of the type 1 interferon-pathway, and when the infection is over, the blockage should stop and go back to normal. But that does not seem to be the case in patients with Parkinson’s Disease. We further demonstrate that this dysregulation leads to a defect in the mitochondrial energy supply, as mentioned before’, says Shohreh Issazadeh-Navikas.

These pathways are crucial for brain activities, but they’re also involved in microbe and viral recognition. They’re crucial for combating COVID-19, for example, and a mutation in a similar gene has been linked to a fatal outcome after getting COVID-19.

The researchers pooled and examined four data sets that looked at the types of genes expressed in neurons from Parkinson’s disease brains. They next looked at which gene patterns were disrupted in Parkinson’s Disease patients, particularly those who had developed PD and dementia.

The primary findings of the combined data were tested in three separate mice models utilizing PIAS2, a negative regulator of the type I interferon pathway that had been identified as one of the essential proteins related to the course of Parkinson’s Disease and dementia in the patients study.

‘We show that a high accumulation of the PIAS2-protein is what is causing the blockage in the pathway, which should have activated the processes responsible for removing damaged protein and mitochondrial garbage’, says Shohreh Issazadeh-Navikas.

‘The accumulation of damaged mitochondrial mass further leads to increase of other toxic proteins. So when we compare patients to same-aged healthy patients without Parkinson’s Disease, we see that this PIAS2-protein is highly expressed in the neurons, which is why this pathway should be evaluated for potential roles in the other forms of familial Parkinson’s Disease that we have not studied here.’

The researchers hope that the findings will drive more research towards understanding the effects of restoring the pathway blockage, which might help to treat dementia and prevent PD. In the future, the Shohreh Group plans to investigate how the route contributes to neuronal homeostasis and survival, as well as how its dysregulation leads to neuronal cell death.

The study was published in Molecular Psychiatry on July 8th, 2021.

Abstract. Familial Parkinson disease (PD) is associated with rare genetic mutations, but the etiology in most patients with sporadic (s)PD is largely unknown, and the basis for its progression to dementia (sPDD) is poorly characterized. We have identified that loss of IFNβ or IFNAR1, the receptor for IFNα/β, causes pathological and behavioral changes resembling PDD, prompting us to hypothesize that dysregulated genes in IFNβ-IFNAR signaling pathway predispose one to sPD. By transcriptomic analysis, we found defective neuronal IFNβ-IFNAR signaling, including particularly elevated PIAS2 associated with sPDD. With meta-analysis of GWASs, we identified sequence variants in IFNβ-IFNAR-related genes in sPD patients. Furthermore, sPDD patients expressed higher levels of PIAS2 mRNA and protein in neurons. To determine its function in brain, we overexpressed PIAS2 under a neuronal promoter, alone or with human α-synuclein, in the brains of mice, which caused motor and cognitive impairments and correlated with intraneuronal phosphorylated (p)α-synuclein accumulation and dopaminergic neuron loss. Ectopic expression of neuronal PIAS2 blocked mitophagy, increased the accumulation of senescent mitochondrial and oxidative stress, as evidenced by excessive oxDJ1 and 8OHdG, by inactivating ERK1/2-P53 signaling. Conversely, PIAS2 knockdown rescued the clinicopathological manifestations of PDD in Ifnb–/– mice on restoring mitochondrial homeostasis, oxidative stress, and pERK1/2-pP53 signaling. The regulation of JAK-STAT2-PIAS2 signaling was crucial for neurite outgrowth and neuronal survival and excitability and thus might prevent cognitive impairments. Our findings provide insights into the progression of sPD and dementia and have implications for new therapeutic approaches.

Discussion. Our findings imply that the dysregulation of PIAS2 potentiates the development of PD on several levels against an array of signaling proteins, the multifaceted functions of which converge to disrupt neuronal homeostasis and functions. Collectively, our novel findings render PIAS2 an exciting target for future therapeutic approaches in PD.

Magalhaes, J., Tresse, E., Ejlerskov, P. et al. PIAS2-mediated blockade of IFN-β signaling: a basis for sporadic Parkinson disease dementia. Mol Psychiatry (2021).

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