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Pharmacological Inhibition of Brain EGFR Activation By a BBB-penetrating Inhibitor, AZD3759, Attenuates α-synuclein Pathology in a Mouse Model of α-Synuclein Propagation.
Tavassoly, Omid; Del Cid Pellitero, Esther; Larroquette, Frederique; Cai, Eddie; Thomas, Rhalena A; Soubannier, Vincent; Luo, Wen; Durcan, Thomas M; Fon, Edward A.
Afiliación
  • Tavassoly O; Department of Chemistry, Simon Fraser University, Burnaby, BC, Canada. otavasso@sfu.ca.
  • Del Cid Pellitero E; McGill Parkinson Program and Neurodegenerative Diseases Group, Montreal Neurological Institute, McGill University, Montréal, QC, Canada. otavasso@sfu.ca.
  • Larroquette F; McGill Parkinson Program and Neurodegenerative Diseases Group, Montreal Neurological Institute, McGill University, Montréal, QC, Canada.
  • Cai E; McGill Parkinson Program and Neurodegenerative Diseases Group, Montreal Neurological Institute, McGill University, Montréal, QC, Canada.
  • Thomas RA; McGill Parkinson Program and Neurodegenerative Diseases Group, Montreal Neurological Institute, McGill University, Montréal, QC, Canada.
  • Soubannier V; Early Drug Discovery Unit, Montreal Neurological Institute, McGill University, Montréal, QC, Canada.
  • Luo W; McGill Parkinson Program and Neurodegenerative Diseases Group, Montreal Neurological Institute, McGill University, Montréal, QC, Canada.
  • Durcan TM; Early Drug Discovery Unit, Montreal Neurological Institute, McGill University, Montréal, QC, Canada.
  • Fon EA; Early Drug Discovery Unit, Montreal Neurological Institute, McGill University, Montréal, QC, Canada.
Neurotherapeutics ; 18(2): 979-997, 2021 04.
Article en En | MEDLINE | ID: mdl-33713002
Aggregation and deposition of α-synuclein (α-syn) in Lewy bodies within dopamine neurons of substantia nigra (SN) is the pathological hallmark of Parkinson's disease (PD). These toxic α-syn aggregates are believed to propagate from neuron-to-neuron and spread the α-syn pathology throughout the brain beyond dopamine neurons in a prion-like manner. Targeting propagation of such α-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-ß. We show here that EGFR regulates the uptake of exogenous α-syn-PFFs and the levels of endogenous α-syn in cell cultures and a mouse model of α-syn propagation, respectively. Thus, we tested the therapeutic potentials of AZD3759, a highly selective BBB-penetrating EGFR inhibitor, in a preclinical mouse model of α-syn propagation. AZD3759 decreases activated EGFR levels in the brain and reduces phosphorylated α-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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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Piperazinas / Quinazolinas / Encéfalo / Barrera Hematoencefálica / Alfa-Sinucleína / Receptores ErbB / Sinucleinopatías Tipo de estudio: Prognostic_studies Límite: Animals / Humans / Male Idioma: En Revista: Neurotherapeutics Asunto de la revista: NEUROLOGIA Año: 2021 Tipo del documento: Article País de afiliación: Canadá Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Piperazinas / Quinazolinas / Encéfalo / Barrera Hematoencefálica / Alfa-Sinucleína / Receptores ErbB / Sinucleinopatías Tipo de estudio: Prognostic_studies Límite: Animals / Humans / Male Idioma: En Revista: Neurotherapeutics Asunto de la revista: NEUROLOGIA Año: 2021 Tipo del documento: Article País de afiliación: Canadá Pais de publicación: Estados Unidos