Investigating natural compounds as regulators of ataxin-3 levels in transgenic models of Machado-Joseph disease (MJD)

<p dir="ltr">Machado-Joseph disease (MJD), also known as spinocerebellar ataxia type 3 (SCA3), is a type of polyglutamine neurodegenerative disease. MJD is an incurable disorder that is inherited through autosomal dominance, and it has particularly high prevalence in the Indigenous communities of north-east Arnhem Land in Australia. Signs and symptoms of MJD begin with cerebellar ataxia, or poor muscular control, before involuntary muscular contraction (dystonia), loss of coordination, slurred speech, and vision impairment also start to impact the affected individual. MJD is caused by an expansion of the CAG trinucleotide repeat in the ATXN3 gene that causes the expression of an abnormal ataxin-3 protein that contains a long polyglutamine (polyQ) repeat region. It is not yet known what this protein does in terms of disease initiation and progression, and there is currently no cure or effective treatment for the disease. It is also not known whether increasing or decreasing ataxin-3 can prevent or delay development of MJD. Therefore, our research aims to provide greater insight in this area, to aid development of a potential cure for MJD. Here, we aimed to investigate natural compounds and their synthetic analogues as potential treatments or cure for the disease, especially due to the importance of bush medicine within Indigenous communities. We hypothesised that natural compounds that decrease the abundance of mutant ataxin-3 protein would have beneficial effects on disease progression. However, we considered that this may also produce a loss of protein function effect that would have negative impacts. We tested the full Davis Natural Product-Based Library, which consists of 512 compounds, using a high throughput screening (HTS) approach, in collaboration with Griffith University. We present here the findings of that screening, including the validation of three hit compounds within further testing on a transgenic MJD zebrafish model of disease. We report that the compounds that were identified as decreasing the abundance of expressed human ataxin-3 protein in the HTS each improved the motor phenotype of the MJD zebrafish in a dose-dependent manner. Agreeably, the compound that increased mutant ataxin-3 abundance within the HTS is seen to worsen the motor phenotype of the MJD zebrafish. We propose that these compounds, and the other hits identified within our study, warrant further investigation for the treatment of MJD, using a range of different preclinical models.</p>