Mitochondrial Malfunction Cause Parkinson’s Disease

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12,000 people in Denmark and 7 to 10 million people worldwide suffer from Parkinson’s Disease (PD). It is the second most common neurogenerative disorder of aging and the most common movement disorder, but the cause of the disease is largely unknown.

In a new study, researchers from the University of Copenhagen show that the most common form of the disease, encompassing 90 to 95 percent of all Parkinson’s Disease cases known as sporadic PD, is caused by a blockage of a pathway that regulates 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.

The blockage leads to an accumulation of high amounts of damaged mitochondria, while not being able to produce enough energy for the cells. It causes neurons to gradually die, which is the reason for the development of Parkinson’s Disease symptoms, and why it leads to dementia.

The blockage is caused by a dysregulation of the immune genes, more specifically a pathway called type 1 interferon, which is normally important for fight against viruses, but now we show that it is also responsible for regulating the energy supply of the nerve cells.

‘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 very important for brain functions, but they are also associated with microbial and virus recognition. For example, they are very important for fighting COVID-19, and a mutation in the related gene has been shown to be linked to a deadly outcome after contracting COVID-19.

The researchers combined and analyzed four data sets, which studied neurons from brains with Parkinson’s Disease and looked at what type of genes they express.

They then looked at which gene patterns were disturbed in patients with Parkinson’s Disease and especially those who had also developed PD with dementia.

In order to test the results, the major findings of the combined data was tried in three different mouse models using a negative regulator of the type I interferon pathway, PIAS2, which had been identified from the patients study as one of the key proteins linked to the progression of Parkinson’s Disease and dementia.

‘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 the study will encourage research to counteract the pathway blockage, which could have a beneficial impact on the disease and towards preventing dementia.

In the next stages, the Shohreh Group will study how the pathway contributes to neuronal homeostasis and survival, as well as how its dysregulation causes neuronal cell death.


Parkinson’s disease (PD) is the second most common age-related neurodegenerative disorder, affecting more than 10 million people worldwide [1]. Most patients develop the disease in a sporadic manner through a complex interaction between genetic and environmental risk factors during ageing. Roughly 5%–10% of PD patients are caused by highly penetrant variants in genes such as PINK1 (encoding PTEN-induced putative kinase 1 [PINK1]) and PARK2 (encoding the E3 ubiquitin ligase Parkin) [2, 3].

This type of PD is referred to as familial PD, and missense variants of VPS35 have been linked to the autosomal dominant form of familial PD [4, 5]. However, the c.1858G > A, p.D620N variant in VPS35 is the only proven pathogenic variant [6]. VPS35 encodes the vacuolar protein sorting-associated protein 35 (VPS35) that, together with VPS26 and VPS29, forms the cargo-selective subcomplex of the retromer complex [7].

The retromer recycles membrane proteins from endosomes to either the Golgi apparatus or the plasma membrane [8]. The p.D620N variant is located in a domain of VPS35 that is essential for protein–protein interactions [7]. Although the variant does not affect the formation of the retromer complex, it has impaired interactions with other factors such as the actin-nucleating WASH (Wiskott-Aldrich syndrome and SCAR homolog) complex [9, 10]. This leads to the altered retromer functioning and deficits in the sorting of cargoes [9–12].

Retromer also participates in the transport of mitochondrial cargoes to lysosomes or peroxisomes via mitochondrial-derived vesicles (MDVs) [13–15]. Previous reports have shown that VPS35 is involved in mitochondrial dynamics, as it recycles the fission protein DLP1 and regulates the level of the fusion protein MFN2 through the transport of mitochondrial E3 ubiquitin ligase 1 (MUL1) [14, 15].

Overexpression of the VPS35 D620N mutant augments mitochondrial fragmentation due to the increased DLP1 activity, whereas VPS35 depletion leads to mitochondrial fragmentation as a result of decreased level of MFN2, which correlates with a reduced mitochondrial respiratory capacity and a decrease in mitochondrial membrane potential [14–16].

Mitochondrial dysfunction plays an integral role in the pathogenesis of both sporadic and familial PD [17–19]. For example, loss-of-function variants of mitochondrial quality control genes such as PINK1 and PARK2 lead to early-onset autosomal recessive PD [2, 3, 20–22]. To maintain the mitochondrial quality, PINK1 is imported through a membrane potential–dependent process, from the outer mitochondrial membrane (OMM) into the inner mitochondrial membrane, where it is constitutively degraded by mitochondrial proteases [23, 24].

However, PINK1 import and cleavage is blocked upon mitochondrial depolarization caused by damage, resulting in the accumulation of PINK1 on the OMM. At the OMM, PINK1 phosphorylates ubiquitin and Parkin, leading to stable recruitment and activation of Parkin onto the mitochondrial surface [21, 24, 25]. Parkin then ubiquitinates different OMM substrates, inducing proteasomal degradation and removal of damaged cargoes via the MDVs-to-lysosome transport and/or mitophagy [26–28].

Mitophagy is a selective type of autophagy in which mitochondria targeted for degradation are sequestered into double-membrane autophagosomes and delivered into lysosomes [29, 30]. This process occurs in different physiological contexts [30]. For instance, most cells continuously undergo basal mitophagy during routine mitochondrial maintenance [31].

However, mitophagy can also be induced as a response to mitochondrial stressors such as mitochondrial depolarization. Notably, the PD-associated proteins PINK1 and Parkin are directly involved in stress-induced mitophagy [21, 24] but not in basal mitophagy [32, 33]. As dopaminergic neurons undergo substantial mitochondrial stress, presumably due to their pacemaker activity [34, 35], the stress-induced mitophagy via PINK1/Parkin has been heavily implicated in the pathogenesis of PD [30].

Given the mitochondrial impairments associated with the p.D620N variant of VPS35 and the role of PINK1 and Parkin in maintaining mitochondrial quality control under stress conditions, we questioned whether the actions of these genes converge into a similar pathway to cause PD. Therefore, we set out to determine whether stress-induced mitophagy via PINK1/Parkin is affected by the VPS35 p.D620N mutant, using VPS35 mutant SH-SY5Y cells carrying the p.D620N variant on one allele, which recapitulates the patient situation.

REFERENCE LINK : https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8204421/


Source: University of Copenhagen

Original Research: Open access.
“PIAS2-mediated blockade of IFN-β signaling: a basis for sporadic Parkinson disease dementia” by Joana Magalhaes, Emilie Tresse, Patrick Ejlerskov, Erling Hu, Yawei Liu, Andrea Marin, Alexia Montalant, Letizia Satriano, Carsten Friis Rundsten, Eva Maria Meier Carlsen, Rasmus Rydbirk, Ali Sharifi-Zarchi, Jesper Bøje Andersen, Susana Aznar, Tomasz Brudek, Konstantin Khodosevich, Marco Prinz, Jean-François Marie Perrier, Manu Sharma, Thomas Gasser & Shohreh Issazadeh-Navikas. Molecular Psychiatry

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