Methacycline displays a strong efficacy in reducing toxicity in a SCA3 Caenorhabditis elegans model.
BACKGROUND
We have previously demonstrated the neuroprotective activity of tetracycline on a Spinocerebellar Ataxia 3 nematode model. Here, we present the screening of a small library of tetracycline congeners in order to identify the most effective compound in preventing ataxin-3 aggregation.


METHODS
We performed the assays on the Josephin Domain as it is directly involved in the onset of fibrillation. We used thioflavin T and solubility assays to spot out the most effective tetracycline congeners; Fourier transform infrared and NMR spectroscopies to characterize their mode of action. We employed an ataxic Caenorhabditis elegans model to evaluate the pharmacological efficacy of tetracycline congeners.


RESULTS
Methacycline was identified as the most effective compound. Like tetracycline, methacycline neither significantly affected the aggregation kinetics nor did it change the secondary structures of the final aggregates but increased the solubility of the aggregated species. Saturation transfer NMR experiments demonstrated methacycline capability to only bind the oligomeric species of Josephin Domain. Competition assays also showed that methacycline binds to the Josephin Domain more tightly than tetracycline. The treatment with methacycline induced a significant improvement in motility and locomotion of the transgenic C. elegans without changing its lifespan. The efficacy was distinctly stronger than that of tetracycline. Noteworthy, unlike tetracycline, methacycline was able to retard aging-related decline in motility of even the healthy worms used.


CONCLUSIONS
The apparent absence of toxic effects displayed by methacycline, along with its stronger efficacy in contrasting expanded ataxin-3 toxicity, makes it a possible candidate for a chronic treatment of the disease.
['Amigoni|Loredana|L|', 'Airoldi|Cristina|C|', 'Natalello|Antonino|A|', 'Romeo|Margherita|M|', 'Diomede|Luisa|L|', 'Tortora|Paolo|P|', 'Regonesi|Maria Elena|ME|']
D000818:Animals D000900:Anti-Bacterial Agents D000067699:Ataxin-3 D017173:Caenorhabditis elegans D007700:Kinetics D008690:Methacycline D008954:Models, Biological D066329:Protein Aggregates D017433:Protein Structure, Secondary
methacycline Caenorhabditis elegans tetracycline ataxin-3 Amyloid aggregation molecular recognition