Huntington’s disease (HD) is a dominantly transmitted neurodegenerative disorder with an average age at onset of 40 years. Children of HD gene carriers have a 50% chance of inheriting the disease. The characteristic symptoms of Huntington’s disease are involuntary choreiform movements, cognitive impairment, mood disorders, and behavioral changes which are chronic and progressive over the course of the illness. (NeuroRx. 2004 Apr Richard H. Myers).
The HD gene provides instructions for making a protein called huntingtin. Although the exact function of this protein is unknown, it appears to play an important role in nerve cells (neurons) in the brain and is essential for normal development before birth. Huntingtin is found in many of the body's tissues, with the highest levels of activity in the brain. Within cells, this protein may be involved in chemical signaling, transporting materials, attaching (binding) to proteins and other structures, and protecting the cell from self-destruction (apoptosis). In the beginning of the HTT gene there is a stretch of CAG trinucleotide repeat. This segment is made up of a series of three DNA building blocks (cytosine, adenine, and guanine) that appear multiple times in a row. Normally, the CAG segment is repeated 10 to 35 times within the gene, but when repeats are higher than 100, disease occurs. The exact mechanism which causes disease due to extended CAG repeats is unclear. Currently, there is no treatment that can stop or reverse the course of Huntington’s disease . During protein translation, ribosomes chain amino acids that are carried by tRNAs molecules. Anima’s Protein Synthesis Monitoring (PSM) technology uses fluorescently labelled tRNA pairs, specifically selected for each target protein. When such a labeled pair enters the ribosome, it emits a light pulse. The light pulses tell us when, where and how much of the target proteins being made by ribosomes, in real time.
As described in the image above, PSM is used to follow the translation of Huntingtin through extended CAG repeats. We monitor possible defects in mutant HTT translation and screen for compounds that may correct the malfunctions in this process.
In cells expressing mutant HTT (lower right panel), a higher FRET signal was observed (compare upper right and left panels) and we have demonstrated that this is correlated with ribosome stalling.
Ribosomes can stall during translation for a number of reasons, each of which triggers protein and mRNA quality control pathways , resulting in the generation of short peptides and mRNA degradation (Lykke-Andersen and Bennett, 2014; Shoemaker and Green, 2012). The protein products of these translational stalls are usually degraded via the ubiquitin-proteasome system. However, under some circumstances and specifically in the case of a mutant Huntingtin, peptides are not degraded but rather accumulate in the cell. This may be the cause of mutant-HTT mediated neuronal damage.
Our discovery program is using our novel technology to discover compounds that may correct ribosome stalling, which we believe may be an underlying cause for the Huntington disease.
Status: Assay development optimization PSM Anima’s technology is currently under optimization for Huntingtin translation inhibitors High Content Screening.