Doxycycline inhibits alpha -synuclein-associated pathologies in vitro and in vivo

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Dominguez-Meijide, Antonio ^{[1, 2, 3]} ; Parrales, Valeria ^[4] ; Vasili, Eftychia ^[1] ; Gonzalez-Lizarraga, Florencia ^[5] ; Konig, Annekatrin ^[1] ; Lazaro, Diana F. ^[1] ; Lannuzel, Annie ^{[4, 6]} ; Haik, Stephane ^{[4, 7]} ; Del Bel, Elaine ^[8] ; Chehin, Rosana ^[5] ; Raisman-Vozari, Rita ^[4] ; Michel, Patrick P. ^[4] ; Bizat, Nicolas ^{[4, 9]} ; Outeiro, Tiago Fleming ^{[1, 10, 11]}

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^[1] Univ Med Ctr Goettingen, Ctr Biostruct Imaging Neurodegenerat, Dept Expt Neurodegenerat, Gottingen - Germany

^[2] Univ Santiago de Compostela, Dept Morphol Sci, Lab Neuroanat & Expt Neurol, IDIS, CIMUS, Santiago De Compostela - Spain

^[3] Networking Res Ctr Neurodegenerat Dis CIBERNED, Madrid - Spain

^[4] Sorbonne Univ, Paris Brain Inst, INSERM, U1127, CNRS, UMR 7225, F-75013 Paris - France

^[5] CONICET UNT SIPROSA, Inst Invest Med Mol & Celular Aplicada IMMCA, San Miguel De Tucuman, Tucuman - Argentina

^[6] Univ Hosp Pointe A Pitre, Neurol Dept, Route Chauvel, F-97139 Abymes, Guadeloupe - France

^[7] Univ Hosp Pitie Salpetriere, AP HP, Cellule Natl Reference Malad Creutzfeldt Jakob, F-75013 Paris - France

^[8] Univ Sao Paulo, Fac Odontol Ribeirao Preto, Dept Basic & Oral Biol, Av Cafe S-N, Sao Paulo - Brazil

^[9] Paris Univ, Fac Pharm Paris, 4 Ave Observ, F-75006 Paris - France

^[10] Max Planck Inst Expt Med, Gottingen - Germany

^[11] Newcastle Univ, Fac Med Sci, Translat & Clin Res Inst, Framlington Pl, Newcastle Upon Tyne NE2 4HH, Tyne & Wear - England

• Tipo de documento: Artigo Científico
• Fonte: Neurobiology of Disease; v. 151, APR 2021.
• Citações Web of Science: 1

Resumo

Parkinson's disease (PD) and dementia with Lewy bodies (DLB) are neurodegenerative disorders characterized by the misfolding and aggregation of alpha-synuclein (aSyn). Doxycycline, a tetracyclic antibiotic shows neuroprotective effects, initially proposed to be due to its anti-inflammatory properties. More recently, an additional mechanism by which doxycycline may exert its neuroprotective effects has been proposed as it has been shown that it inhibits amyloid aggregation. Here, we studied the effects of doxycycline on aSyn aggregation in vivo, in vitro and in a cell free system using real-time quaking induced conversion (RT-QuiC). Using H4, SH-SY5Y and HEK293 cells, we found that doxycycline decreases the number and size of aSyn aggregates in cells. In addition, doxycycline inhibits the aggregation and seeding of recombinant aSyn, and attenuates the production of mitochondrial-derived reactive oxygen species. Finally, we found that doxycycline induces a cellular redistribution of aggregates in a C.elegans animal model of PD, an effect that is associated with a recovery of dopaminergic function. In summary, we provide strong evidence that doxycycline treatment may be an effective strategy against synucleinopathies. (AU)

• Processo FAPESP: 14/25029-4 - Estudo da contribuição do processo inflamatório na discinesia induzida por L-DOPA na Doença de Parkinson
• Beneficiário: Elaine Aparecida Del Bel Belluz Guimarães
• Modalidade de apoio: Auxílio à Pesquisa - Temático