Parkinson’s and the immune system

Summary: Researchers provide new evidence of the link between Parkinson’s disease and the immune system.

Source: RUB

A research team was thus able to provide further evidence that there are interfaces between the nervous system and the immune system. The researchers hope that the protagonists or antagonists of this signaling pathway may be suitable for therapeutic interventions. They report on this in the cover story in the journal Science Signaling on 4 February 2020.

Genes protect nerve cells against cell death

The Parkin gene protects nerve cells against functional impairment and cell death. It particularly ensures that mitochondria, cell organelles that are responsible for energy production, remain intact and that damaged mitochondria are removed. PACRG is located next to the Parkin gene in the genome. Both genes share what is called a promotor, which regulates the expression of the genes. Parkin and PACRG are thus expressed in a similar pattern.

“Little has been known about PACRG so far, so we investigated what functions this gene has,” says Konstanze Winklhofer. Her team found that, unlike Parkin, PACRG has no influence on the elimination of damaged mitochondria, but, like parkin, is able to protect nerve cells from cell death.

Parkin and PACRG regulate a signaling pathway of the innate immune system

Further investigations into the mechanism of action showed that PACRG regulates a signaling pathway that is stimulated by tumor necrosis factor (TNF). This results in the activation of the transcription factor NF-κB, which ensures the increased formation of pro-survival proteins. Both Parkin and PACRG have an effect on an essential protein complex of this signaling pathway, called Lubac (linear ubiquitin chain assembly complex). Lubac is required for efficient signal transduction by modifying components of the NF-κB signaling pathway with linear ubiquitin chains.

This shows the anatomy of two bodies

Both genes share what is called a promotor, which regulates the expression of the genes. Parkin and PACRG are thus expressed in a similar pattern. Image is in the public domain.

The TNF-NF-κB signaling pathway not only regulates cell death but also plays an important role in the innate immune system. It prevents the spreading of certain bacteria that invade host cells, such as salmonella, linked to foodborne infections, or mycobacteria, which cause tuberculosis or leprosy. “Interestingly, sequence variations in the Parkin and PACRG genes have been described that lead to an increased susceptibility to these bacterial infections and are associated with severe courses of salmonella or mycobacterial infections,” explains Konstanze Winklhofer. The current findings thus provide a plausible explanation for these observations and confirm that there are interfaces between the nervous system and the immune system. Their protagonists or antagonists could be suitable targets for therapeutic interventions.

Funding: The work was funded by the German Research Foundation (WI-2111/4, WI-2111/6, MA-3257/5, TA-167/6, SFB 1177, project C2), the Michael J. Fox Foundation (Parkin Biology 2013 Grant and Grant ID 16293), the Munich Cluster for Systems Neurology, the Loewe programme Ub-Net, the North Rhine-Westphalia project Protein Unit for Research in Europe (Pure), and the German Research Foundation as part of the Excellence Strategy of the Federal and State Governments – EXC 2033 – project number 390677874 – Resolv.

About this neuroscience research article

Source:
RUB
Media Contacts:
Konstanze Winklhofer – RUB
Image Source:
The image is in the public domain.

Original Research: Closed access
“The Parkin-coregulated gene PACRG promotes TNF signaling by stabilizing the linear ubiquitin chain assembly complex”. Jens Meschede et al.
Science Signaling doi:10.1126/scisignal.aav1256.

Abstract

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The Parkin-coregulated gene (PACRG), which encodes a protein of unknown function, shares a bidirectional promoter with Parkin (PRKN), which encodes an E3 ubiquitin ligase. Because PRKN is important in mitochondrial quality control and protection against stress, we tested whether PACRG also affected these pathways in various cultured human cell lines and in mouse embryonic fibroblasts. PACRG did not play a role in mitophagy but did play a role in tumor necrosis factor (TNF) signaling. Similarly to Parkin, PACRG promoted nuclear factor κB (NF-κB) activation in response to TNF. TNF-induced nuclear translocation of the NF-κB subunit p65 and NF-κB–dependent transcription were decreased in PACRG-deficient cells. Defective canonical NF-κB activation in the absence of PACRG was accompanied by a decrease in linear ubiquitylation mediated by the linear ubiquitin chain assembly complex (LUBAC), which is composed of the two E3 ubiquitin ligases HOIP and HOIL-1L and the adaptor protein SHARPIN. Upon TNF stimulation, PACRG was recruited to the activated TNF receptor complex and interacted with LUBAC components. PACRG functionally replaced SHARPIN in this context. In SHARPIN-deficient cells, PACRG prevented LUBAC destabilization, restored HOIP-dependent linear ubiquitylation, and protected cells from TNF-induced apoptosis. This function of PACRG in positively regulating TNF signaling may help to explain the association of PACRG and PRKN polymorphisms with an increased susceptibility to intracellular pathogens.

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