IDENTIFICATION OF NOVEL DISEASE MODULATORS OF HUNTINGTON’S DISEASE - APPLICATION OF DIRECT REPROGRAMMING-BASED IN VITRO MODEL DERIVED FROM PATIENTS

Background:

We live in an ageing society - as a result, we are observing an exponential increase in age-related diseases, including neurodegenerative diseases. Unfortunately, despite extensive research in the field, these diseases are still largely incurable. Huntington's disease is the most common monogenic neurodegenerative disease. It is caused by the expansion of the polyQ chain in the huntingtin protein, which leads to a disturbance in the conformation and accumulation of the protein in the cell and ultimately cell death. The most affected in the disease are the medium spiny neurons of the striatum.

The fact of protein aggregation in the cell observed in neurodegenerative diseases indicates disturbances in the processes of protein quality control (PQC) in these diseases. It can therefore be hypothesized that strengthening cellular proteostasis and naturally occurring processes of protein quality control could bring a therapeutic effect. In accordance with this hypothesis, the aim of work is to better understand the molecular basis of protein quality control disorders in Huntington's disease and to identify new modulators of the disease, which we hope may then lead to the definition of new potential therapeutic targets.

In vitro model:

The lack of success in clinical trials of a number of therapeutic approaches that are effective preclinically, observed over the years, was partly due to the imperfection of the neurodegenerative disease models used. A milestone towards creating better models was the discovery of the possibility of reprogramming the patient's somatic cells, e.g. skin cells, to neurons, obtaining a model that preserves the genetic background of the human disease. The vast majority of models used here include passing through the pluripotency stage - returning to the embryonic state. Unfortunately, this erases the sign of age, a key risk factor in neurodegeneration. Therefore, we use an alternative model, the model of direct reprogramming from fibroblasts to neurons, which does not lose the sign of age and much better reproduces clinically significant disease phenotypes. This model was created by Andrew Yoo, with whom we cooperate, it includes the use of a miRNA cocktail, which, through chromatin remodeling, turns off the identity of fibroblasts and turns on the neuronal program. Additionally, specific transcription factors direct cells specifically to medium spiny neurons, i.e. those most affected by the disease.