Research projects

Results of two previous projects, Ref: PCIG11-GA-2012-322034 and Ref: 559, allowed us to establish the hypothesis that AMPK activation, through a combination of compounds, could be a potential therapeutic strategy in Huntington's disease (HD), and perhaps in other neurodegenerative diseases. Carry out preclinical trials, in HD models, through the synergistic activation of AMPK, using a combination of compounds that modulate the activity of this enzyme, to reduce the toxicity induced by mutant huntingtin.

Results:

1- We have shown that activating AMPK in Caenorhabditis elegans, using low doses of metformin and salicylate, results in the activation of autophagy, and that it results in the reduction of polyglutamine aggregates (polyQs). In addition, it rescues phenotypes induced by α-synuclein, which could be relevant in Parkinson's disease.

2-A synthetic drug, indole IND1316, is capable of reducing HD-associated phenotypes in HD model worms and mice.

3-Extracts from the Bacopa monnieri plant are able to reduce polyQ toxicity in C. elegans, which could be the basis for future HD treatments, if they are shown to work in mammals.

4-Thanks to a collaboration with Dr. Antonio Sánchez (Polytechnic University of Valencia), a robot capable of evaluating RNA-induced phenotypes containing CAG expansions has been developed. This equipment will serve us in the future to carry out experiments in an automated way.

5-Another collaboration with Dr. Gisela Nogales from the Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol, showed that the RAN translation effect could not be relevant in type I myotonic dystrophy.

6-Literature review recapitulating the importance of oxidative stress in HD, and possible therapeutic strategies.

7- We have performed lipidomics studies from fat from HD mouse models (zQ175), and healthy controls, treated and untreated with combinations of metformin and aspirin. We have observed that there are substantial differences between the two models. These results are pending publication.

8- In collaboration with Bionos Biotech (an IIS-La Fe spin-off biotechnological company) we have characterized a compound whose patent is being exploited by this company, 4QMn, in in vitro and in vivo models of HD. This compound activates autophagy and the proteasome, and alleviates many of the symptoms of HD in these models.