Science and Technology Production
Congress
Authorship
Raisman-Vosari, Rita
;
Teran, María del Milagro
;
Tomas-Grau, Rodrigo Hernán
;
Ploper, Diego
;
Besnault, Pierre
;
SOLIZ SANTANDER, SILVANA ESTAFANÍA
;
Rose, C.
;
Luna Mercado, Álvaro
;
Villacé, P.
;
Ávila, César Luís
;
Brunel, J.
;
Ferrié, L.
;
Salado, C.
;
Michel, P.
;
Figadère, Bruno
;
Chehín, Rosana Nieves
Date
2024
Publishing House and Editing Place
AD/PD 2024
Summary
Information provided by the agent in
SIGEVA
Alpha-synuclein (α-Syn) aggregation is a hallmark of neurodegenerative diseases like Parkinson´s. Doxycycline (DOX), a tetracycline, has shown potential in inhibiting α-Syn aggregation, but its antibiotic properties limit its therapeutic use. To address this, we developed a non-antibiotic tetracycline derivative, DDox, which aimed to mitigate α-Syn aggregation and offer a safe alternative for disease models. Methods: DDox was synthesized through the removal of the dimeth...
Alpha-synuclein (α-Syn) aggregation is a hallmark of neurodegenerative diseases like Parkinson´s. Doxycycline (DOX), a tetracycline, has shown potential in inhibiting α-Syn aggregation, but its antibiotic properties limit its therapeutic use. To address this, we developed a non-antibiotic tetracycline derivative, DDox, which aimed to mitigate α-Syn aggregation and offer a safe alternative for disease models. Methods: DDox was synthesized through the removal of the dimethylamino substituent at position 4 on ring A and the reduction of the hydroxyl group at C12a. We assessed DDox´s antibiotic activity against Gram(+) and (-) bacterial strains and evaluated its toxicity on the SHSY5Y cell line using MTT assay. The capability of DDox at interfering with α-Syn aggregation was assessed through: fluorescent spectroscopy, TEM and immunofluorescence in SHSY5Y cells. Additionally, we studied DDox effects on α-Syn seeding in SH-SY5Y-aS-RFP cells treated with α-Syn preformed fibrils (α-Syn-PFF), its impact on the uptake of fluorescently-labeled α-Syn-PFF and on α-Syn-PFFtriggered lysosomal stress by confocal microscopy. Results:The chemical modifications that gave rise to DDox effectively diminished antibiotic activity against both Gram (+) and Gram (-) bacterial strains while reducing its toxicity on the SHSY5Y cell line. It outperformed DOX at inhibiting α-Syn amyloid aggregation. In cellular models, DDox reduced α-Syn aggregate formation induced by α-Syn-PFF.Notably, DDox exhibited previously unreported properties by inhibiting α-Syn-PFF uptake and α-Syn-PFF-triggered lysosomal stress, demonstrating its potential in PD models. Conclusions: In summary, DDox, a novel tetracycline, is non-toxic and exhibited limited antibiotic activity. It also improved α-Syn associated phenotypes and showed anti-inflammatory abilities. These findings position DDox as a promising candidate for preclinical studies of synucleinopathies like PD, offering a potential solution to the antibiotic hurdle associated with DOX.
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Key Words
TETRACYCLINESDOXYCICLINEPREFORMED FIBRILSCELL'S UPTAKEALPHA-SYNUCLEINPARKINSON´S DISEASE