HUNTINFISH · Generation of new zebrafish models for the study of the pathogenesis of Huntington´s disease and for the identification of new therapeutic targets.

Generation of new zebrafish models for the study of the pathogenesis of Huntington´s disease and for the identification of new therapeutic targets.

The misfolding and aggregation of intracellular proteins is a feature of many late-onset neurodegenerative diseases, called proteinopathies. These include Alzheimer’s disease, Parkinson’s disease, tauopathies and Huntington’s Disease (HD). HD is one of ten known neurodegenerative diseases caused by (CAG)n trinucleotide tract expansions that encode abnormally long polyglutamine (polyQ) tracts and occurs in about 5-10 cases per 100,000 persons. Currently, there are no effective strategies that slow or prevent the neurodegeneration resulting from these diseases in humans. These diseases are predicted to cause increasing economic and social burdens on society particularly as lifespan increases, hence the need for a better understanding of their biology and identification of therapeutic targets. Since HD is a dominant monogenetic disorder, modelling this disease in vitro and in vivo is relatively straightforward and it has been already demonstrated that small molecules that ameliorate HD pathology are also effective in other neurodegenerative diseases, which simply means that the findings in HD models have relevance not only to HD but potentially to all proteinopathies. Historically, mice have been used to model human diseases because of their physiological, anatomical and genomic similarities to humans. Therefore, the majority of studies in HD have been performed using different mouse models expressing various species of human huntingtin. Although these models have played an important role in providing accurate and experimentally accessible systems to study multiple aspects of disease pathogenesis and to test potential therapeutic treatments, there are aspects that are limiting or even impeding the usage of this model to further study. The zebrafish model has unique characteristics that circumvent many of the limitations found in rodents. As a vertebrate it is excellent for modelling human diseases, it is easy to manipulate pharmacologically and genetically to generate new transgenic lines, its development is fast, its optical transparency facilitates in vivo imaging assays and what is very important it is ideal for high throughput drug screening. Therefore, the main objective of this project is to generate and characterize new zebrafish transgenic lines of HD expressing wild-type and mutant forms of human exon-1 huntingtin, combined with Dendra fluorescent protein, in whole body, neurons and glia and use them to compare the half-lives and in vivo degradation kinetics under basal conditions or under autophagy- or proteasome-inhibition/stimulation conditions. Moreover, we propose to study the role of neuroinflammation and the inflammasomes in the pathogenesis of HD using the newly generated zebrafish transgenic lines, and finally we will test the efficacy of likely protective compounds previously identified in the lab as potential new treatments for HD. Summarizing the final conclusions of this project, I have been able to successfully generate and characterize zebrafish models for HD, that are clearly showing many aspects of the disease, including huntingtin aggregation, shorter life span, increased neuronal cell death or behavioural hyperactivity. Moreover, I have discovered a novel pathway responsible for accelerated early development in mutant HD fish and I am identifying the mechanism for this which may be suitable to be used in the future as a human disease biomarker. Finally, I have tested in our model five protective compounds, previously identified in the lab, from which two of them has given promising results as a potential new treatment for HD.

Data: CORDIS, © European Union