Objective: To investigate whether the pharmacological inhibition of unfolded protein response (UPR) pathway would be beneficial in cellular model of synucleinopathies.

Background: It has been shown that the UPR is activated in many neurodegenerative diseases including Alzheimer’s disease (AD) and Parkinson’s disease (PD) in post mortem human brains as well as in numerous animal and cell models, suggesting that the neurons are subjected to endoplasmic reticulum (ER) stress. Recently, we have shown that UPR pathway is activated to a greater extent when AD- and PD-type pathologies occur simultaneously, in such cases as PD with dementia (PDD) and dementia with Lewy bodies (DLB), in comparison to AD and control subjects. To further support UPR as a tantalising option for the general treatment for neurodegenerative diseases that would be independent of any disease-specific mechanisms, it was shown that inhibiting a key mediator of UPR pathway by a specific protein kinase RNA (PKR)-like ER kinase (PERK) inhibitor prevented UPR-mediated translational repression and abrogated development of clinical signs of prion disease in mice, with neuroprotection throughout the mouse brain.

Methods: Human SH-SY5Y neuroblastoma cells were transfected to over-express either amyloid precursor protein (APP) or α-synuclein. Cells were transfected with pcDNA3.1 (-) plasmids containing APP Swedish KM670/671NL double mutation (APPswe) to model AD-type pathology. To mimic PD pathology, different sets of cells will be transfected with plasmids containing human α-synuclein cDNA. Cells will be treated with a PERK-specific inhibitor, GSK2606414, then the level of proteins that are involved in the activation of UPR: PERK, phosphorylated PERK (p-PERK), and GRP78/BiP, will be quantified using Western blot.

Results: GSK2606414 treatment did not alter the level of GRP78/BiP protein in cells expressing APPswe mutation compared to its wildtype. The levels of PERK and p-PERK protein are currently being quantified in the same type of cells, and all of these protein levels will also be analysed in α-synuclein over-expressing cells.

Conclusions: Preliminary data suggest that the GSK2606414 does not alter the GRP78/BiP protein level in AD cellular model. However, further analyses may reveal the effect of the drug in both AD- and PD cellular models. The results from this study will be of high importance as potential therapeutic targets may be discovered.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/the-unfolded-protein-response-pathway-as-a-possible-therapeutic-target-for-the-synucleinopathies/