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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

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

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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]
Total Authors: 11
[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
Total Affiliations: 3
Document type: Journal article
Source: SCIENTIFIC REPORTS; v. 10, n. 1 NOV 20 2020.
Web of Science Citations: 0

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)

FAPESP's process: 17/24304-0 - New perspectives in the use of drugs that modify atypical neurotransmitters in the treatment of neuropsychiatric disorders
Grantee:Francisco Silveira Guimaraes
Support Opportunities: Research Projects - Thematic Grants
FAPESP's process: 18/03482-0 - The action of cannabinoid drugs in glial-derived neuroinflammation process: a link to L-dopa-induced dyskinesia
Grantee:Maurício dos Santos Pereira
Support Opportunities: Scholarships abroad - Research Internship - Post-doctor
FAPESP's process: 14/25029-4 - Contribution of the neuroinflamation to L-DOPA induced dyskinesia
Grantee:Elaine Aparecida Del Bel Belluz Guimarães
Support Opportunities: Research Projects - Thematic Grants
FAPESP's process: 17/14207-7 - The action of cannabinoid drugs in L-dopa-induced dyskinesia: analysis of neuroinflammation and glutamate release in glial cells
Grantee:Maurício dos Santos Pereira
Support Opportunities: Scholarships in Brazil - Post-Doctoral