CMT-3 targets different alpha-synuclein aggregates mitigating their toxic and inflammogenic effects

Autor(es):Mostrar menos -

Gonzalez-Lizarraga, Florencia L. ^[1] ; Ploper, Diego ^[1] ; Avila, Cesar L. ^[1] ; Socias, Sergio B. ^[1] ; dos-Santos-Pereira, Mauricio ^[2] ; Machin, Belen ^[1] ; Del-Bel, Elaine ^[2] ; Michel, Patrick Pierre ^[3] ; Pietrasanta, I, Lia ; Raisman-Vozari, Rita ^[3] ; Chehin, Rosana ^[1]

Afiliação do(s) autor(es)

^[1] CONICET UNT SIPROSA, Inst Invest Med Mol & Celular Aplicada IMMCA, Pasaje Dorrego 1080, RA-4000 San Miguel De Tucuman, Tucuman - Argentina

^[2] Univ Sao Paulo, Fac Odontol Ribeirao Preto, Ribeirao Preto - Brazil

^[3] Sorbonne Univ UM75, Paris Brain Inst, Inserm U 1127, CNRS UMR 7225, Paris - France

• Tipo de documento: Artigo Científico
• Fonte: SCIENTIFIC REPORTS; v. 10, n. 1 NOV 20 2020.
• Citações Web of Science: 0

Resumo

Parkinson's disease (PD) is a neurodegenerative disorder for which only symptomatic treatments are available. Repurposing drugs that target alpha -synuclein aggregation, considered one of the main drivers of PD progression, could accelerate the development of disease-modifying therapies. In this work, we focused on chemically modified tetracycline 3 (CMT-3), a derivative with reduced antibiotic activity that crosses the blood-brain barrier and is pharmacologically safe. We found that CMT-3 inhibited alpha -synuclein amyloid aggregation and led to the formation of non-toxic molecular species, unlike minocycline. Furthermore, CMT-3 disassembled preformed alpha -synuclein amyloid fibrils into smaller fragments that were unable to seed in subsequent aggregation reactions. Most interestingly, disaggregated species were non-toxic and less inflammogenic on brain microglial cells. Finally, we modelled the interactions between CMT-3 and alpha -synuclein aggregates by molecular simulations. In this way, we propose a mechanism for fibril disassembly. Our results place CMT-3 as a potential disease modifier for PD and possibly other synucleinopathies. (AU)

• Processo FAPESP: 17/24304-0 - Novas perspectivas no emprego de fármacos que modificam neurotransmissores atípicos no tratamento de transtornos neuropsiquiátricos
• Beneficiário: Francisco Silveira Guimaraes
• Modalidade de apoio: Auxílio à Pesquisa - Temático
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• Beneficiário: Maurício dos Santos Pereira
• Modalidade de apoio: Bolsas no Exterior - Estágio de Pesquisa - Pós-Doutorado
• 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
• Processo FAPESP: 17/14207-7 - A ação de fármacos canabinóides na discinesia induzida por l-dopa: análise da neuroinflamação e liberação de glutamato em células gliais
• Beneficiário: Maurício dos Santos Pereira
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado