Biology subjects

Schurr, E.

Publications and source records attributed to Schurr, E..

5 recordsLinked to original sources

bioRxiv2026

STING dampens the unfolded protein response to enable the presentation of self-antigens on MHC-I during inflammation.

A growing body of evidence supports the contribution of the long-lasting adaptive immune system in Parkinsons disease (PD). We showed that the PD-associated protein PINK1 negatively regulates the presentation of mitochondrial antigens (MitAP) on MHC-I molecules. In vivo evidence indicated that MitAP activation in mice, in the absence of PINK1, led to cytotoxic CD8+ T cell stimulation and severe motor impairments, reversible by L-DOPA. We show here that following TLR4 activation, MitAP is engaged through a pathway involving cGAS-STING, which acts as a rheostat to dampen the unfolded protein response (UPR). Without STING, the stress response is amplified, leading to a translational attenuation that inhibits the expression of XBP1s, a transcription factor required for MitAP. STING activity also regulates the repertoire of peptides displayed at the cell surface during inflammation, highlighting a potential role in immunosurveillance. These findings establish STING and the UPR as key immune regulators targetable for therapeutic intervention during autoimmune diseases and PD.

immunology↗

bioRxiv2025

LRRK2G2019S acts as a dominant interfering mutant in the context of iron overload

Altered iron homeostasis has long been implicated in Parkinsons Disease (PD), although the mechanisms have not been clear. Given the critical role of PD-related activating mutations in LRRK2 (leucine-rich repeat protein kinase 2) within membrane trafficking pathways we examined the impact of a homozygous mutant LRRK2G2019S on iron homeostasis within the RAW macrophage cell line with high iron capacity. Proteomics analysis revealed a dysregulation of iron-related proteins in steady state with highly elevated levels of ferritin light chain and a reduction of ferritin heavy chain. LRRK2G2019S mutant cells showed efficient ferritinophagy upon iron chelation, but upon iron overload there was a near complete block in the degradation of the ferritinophagy adaptor NCOA4. These conditions lead to an accumulation of phosphorylated Rab8 at the plasma membrane, which is selectively inhibited by LRRK type II kinase inhibitors. Iron overload then leads to increased oxidative stress and ferroptotic cell death. These data implicate LRRK2 as a key regulator of iron homeostasis and point to the need for an increased focus on the mechanisms of iron dysregulation in PD.

cell biology↗

bioRxiv2023

LRRK2 regulates the activation of the unfolded protein response and antigen presentation in macrophages during inflammation

While the contribution of inflammation in the pathological process leading to Parkinsons disease (PD) is well established, a growing body of evidence supports a role for the long-lasting adaptive immune system in the disease. We showed that, in inflammatory conditions, the PD-proteins PINK1 and Parkin negatively regulate the presentation of mitochondrial antigens on MHC I molecules, a process referred to as MitAP (Mitochondrial Antigen Presentation). In the absence of PINK1, over-activation of this pathway in antigen-presenting cells (APCs) engages autoimmune mechanisms leading to the establishment of cytotoxic CD8+ T cells. Co-culture of dopaminergic neurons (DNs) with these T cells led to neuronal cell death, suggesting that the MitAP in DNs made them susceptible to T cell-mediated destruction. In the present study, we used a pharmacological and genetic approach to characterize the MitAP pathway at the molecular level. We showed that this antigen presentation pathway is induced in APCs in response to inflammatory signals through the sequential activation of TLR4, cGAS-STING and the Unfolded Protein Response (UPR). A "UPR motif" present on a STING cytoplasmic domain was shown to specifically activate the UPR sensor IRE1. Remarkably, the PD-related protein LRRK2, acted with STING upstream of the UPR to regulate the transition from innate to adaptive immunity, thereby identifying this PD-related protein as a key player in the immune response during inflammation.

immunology↗

bioRxiv2019

Pleiotropic effects for Parkin and LRRK2 in leprosy type-1 reactions and Parkinson’s disease

Type-1 reactions (T1Rs) are pathological inflammatory episodes and main contributors to nerve damage in leprosy. Here, we evaluate the gene-wise enrichment of rare protein altering variants in seven genes where common variants were previously associated with T1R. We selected 474 Vietnamese leprosy-patients of which 237 were T1R-affected and 237 were T1R-free matched controls. Gene-wise enrichment of nonsynonymous variants was tested with both kernel based (SKAT) and burden methods. Of the seven genes tested two showed statistical evidence of association with T1R. For the LRRK2 gene an enrichment of nonsynonymous variants was observed in T1R-free controls (p O_SCPCAPSKAT-OC_SCPCAP= 1.6x10-4). This gene-wise association was driven almost entirely by the gain of function variant R1628P (p = 0.004; OR = 0.29). The second gene-wise association was found for the Parkin coding gene PRKN (formerly PARK2) where seven rare variants were enriched in T1R-affected cases (p O_SCPCAPSKAT-OC_SCPCAP = 7.4x10-5). Mutations in both PRKN and LRRK2 are known causes of Parkinsons Disease (PD). Hence, we evaluated to what extent such rare amino acid changes observed in T1R are shared with PD. We observed that nonsynonymous T1R-risk mutations in Parkin were enriched for amino acid mutations implicated in PD (p = 1.5x10-4). Hence, neuro-inflammation in PD and peripheral nerve damage due to inflammation in T1R share overlapping mechanisms of pathogenicity.

genetics↗

bioRxiv2018

Natural selection contributed to immunological differences between human hunter-gatherers and agriculturalists

The shift from a hunter-gatherer (HG) to an agricultural (AG) mode of subsistence is believed to have been associated with profound changes in the burden and diversity of pathogens across human populations. Yet, the extent to which the advent of agriculture may have impacted the evolution of the human immune system remains unknown. Here we present a comparative study of variation in the transcriptional responses of peripheral blood mononuclear cells to bacterial and viral stimuli between Batwa rainforest hunter-gatherers and Bakiga agriculturalists from Uganda. We observed increased divergence between hunter-gatherers and agriculturalists in the transcriptional response to viruses compared to that for bacterial stimuli. We demonstrate that a significant fraction of these transcriptional differences are under genetic control, and we show that positive natural selection has helped to shape population differences in immune regulation. Across the set of genetic variants underlying inter-population immune response differences, however, the signatures of positive selection were disproportionately observed in the rainforest hunter-gatherers. This result is counter to expectations based on the popularized notion that shifts in pathogen exposure due to the advent of agriculture imposed radically heightened selective pressures in agriculturalist populations.

evolutionary biology↗