Identification of Bioactive Compounds Activating Mtf1

Huntington's Disease (HD) is an incurable autosomal dominant neurodegenerative disease caused by trinucleotide repeat expansion in the huntingtin gene (HTT), which results in the production of a mutant form of HTT protein. Mutant HTT (mHTT) forms aggregates, alters gene transcription and induces mitochondrial dysfunction. The hall mark of HD is the degeneration of medium spiny neurons in the striatum, leading to brain atrophy and the onset of motor and psychiatric symptoms. Metal regulatory transcription factor 1 (MTF1), a transcription factor with a key role in regulating metal homeostasis and in detoxification systems, has been recently identified as a potential suppressor of mHTT toxicity. Activating endogenous MTF1 represents a promising therapeutic strategy in neurodegenerative diseases. In this study, I leveraged mouse embryonic stem cells (mESCs) as a biological model to perform a screening of possible bioactive compounds predicted to activate Mtf1. Metallothioneins (Mts) were used as readouts to get insights on the activation of Mtf1. One compound stood out for its ability to activate Mtf1 and might help reduce the toxic effects of mHTT. These findings contribute to the development of novel therapeutic strategies targeting MTF1, with broader implications for the treatment of HD and different neurodegenerative disorders.