Pharmacological Inhibition of Brain EGFR Activation By a BBB-penetrating Inhibitor, AZD3759, Attenuates alpha-synuclein Pathology in a Mouse Model of alpha-Synuclein Propagation
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| Authors: | Tavassoly, O; Pellitero, ED; Larroquette, F; Cai, E; Thomas, RA; Soubannier, V; Luo, W; Durcan, TM; Fon, EA |
| Year: | 2021 |
| Journal: | Neurotherapeutics 18: 979-997 Article Link (DOI) PubMed |
| Title: | Pharmacological Inhibition of Brain EGFR Activation By a BBB-penetrating Inhibitor, AZD3759, Attenuates alpha-synuclein Pathology in a Mouse Model of alpha-Synuclein Propagation |
| Abstract: | Aggregation and deposition of alpha-synuclein (alpha-syn) in Lewy bodies within dopamine neurons of substantia nigra (SN) is the pathological hallmark of Parkinson's disease (PD). These toxic alpha-syn aggregates are believed to propagate from neuron-to-neuron and spread the alpha-syn pathology throughout the brain beyond dopamine neurons in a prion-like manner. Targeting propagation of such alpha-syn aggregates is of high interest but requires identifying pathways involving in this process. Evidence from previous Alzheimer's disease reports suggests that EGFR may be involved in the prion-like propagation and seeding of amyloid-beta. We show here that EGFR regulates the uptake of exogenous alpha-syn-PFFs and the levels of endogenous alpha-syn in cell cultures and a mouse model of alpha-syn propagation, respectively. Thus, we tested the therapeutic potentials of AZD3759, a highly selective BBB-penetrating EGFR inhibitor, in a preclinical mouse model of alpha-syn propagation. AZD3759 decreases activated EGFR levels in the brain and reduces phosphorylated alpha-synuclein (pSyn) pathology in brain sections, including striatum and SN. As AZD3759 is already in the clinic, this paper's results suggest a possible repositioning of AZD3759 as a disease-modifying approach for PD. |
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