Objective: To study a possible association between polymorphisms of the genes coding for proteins involved in the UPR and the development of PD or PD motor and non-motor symptoms.

Background: The accumulation of α -synuclein in Parkinson’s disease (PD) leads to the stress of endoplasmic reticulum (ER) [1-3]. The resulting cellular response is called “Unfolded Protein Responce” (UPR). UPR is activated with the aim of reducing protein synthesis and simultaneously stimulate the prodyction of proteins that mediate apoptosis to reduce protein aggregation. PERK (PKR-like ER kinase) and the transcription factor EIF2A are the main mediator of the UPR.

Method: The study sample included a total sample size of 1666 subjects with 960 PD patients and 506 age/gender-matched healthy controls.

The analysis focused on the genetic variants (SNV) of genes coding for proteins involved in the UPR (EIF2AK3, LRRK2, ATF4, ATF6, XBP1, BCL2, EIF2A, ERN1). The DNA was extracted from the blood samples and the Open Array ™ technology allowed a massive and simultaneous genotyping of all the samples under examination.

Results: We found 51 SNVs concern UPR pathways. In particular, rs6750998, the genetic variant of EIF2AK3 coding for PERK, and rs2626, rs4343650, rs1132979, rs1049947, the genetic variants of EIF2A coding for eIF2α, showed a statistically significant association with susceptibility to PD.

Conclusion: Our study confirms the involvement of UPR and in particular of the PERK pathway in the development of PD. The PERK pathway represents a potential target for the development of new therapeutic strategies for both neuroprotective and symptomatologic purposes [4].

References: 1. Ghemrawi R, Khair M. Endoplasmic Reticulum Stress and Unfolded Protein Response in Neurodegenerative Diseases. Int J Mol Sci. 2020 Aug 25;21(17):6127.
2. Toyofuku T, Okamoto Y, Ishikawa T, Sasawatari S, Kumanogoh A. LRRK2 regulates endoplasmic reticulum-mitochondrial tethering through the PERK-mediated ubiquitination pathway. EMBO J. 2020 Jan 15;39(2):e100875
3. Xiang C, Wang Y, Zhang H, Han F. The role of endoplasmic reticulum stress in neurodegenerative disease. Apoptosis. 2017 Jan;22(1):1-26.
4. Halliday M, Radford H, Zents KAM, Molloy C, Moreno JA, Verity NC, Smith E, Ortori CA, Barrett DA, Bushell M, Mallucci GR. Repurposed drugs targeting eIF2α-P-mediated translational repression prevent neurodegeneration in mice. Brain. 2017 Jun 1;140(6):1768-1783.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/the-role-of-the-unfolded-protein-response-and-the-perk-pathway-in-parkinsons-disease-study-of-genetic-polymorphisms/