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

Author(s):Show less -

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]

Affiliation

^[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

• Document type: Journal article
• Source: SCIENTIFIC REPORTS; v. 10, n. 1 NOV 20 2020.
• Web of Science Citations: 0

Abstract

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 type: 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 type: 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 type: Research Projects - Thematic Grants
• FAPESP's process: 17/14207-7 - THE ACTION OF CANNABINOID DRUGS IN L-DOPA-INDUCED DISCINESIA: ANALYSIS OF NEUROINFLAMATION AND GLUTAMATE RELEASE IN GLIAL CELLS
• Grantee: Maurício dos Santos Pereira
• Support type: Scholarships in Brazil - Post-Doctorate