Polyglutamine Disorders

Sara Duarte-Silva, Patrícia Maciel, Duarte-Silva, Sara, Maciel, Patrícia

Machado-Joseph disease (MJD), also known as Spinocerebellar Ataxia type 3 (SCA3), is the most common autosomal dominant ataxia worldwide. MJD integrates a large group of disorders known as polyglutamine diseases (polyQ). To date, no effective treatment exists for MJD and other polyQ diseases. Nevertheless, researchers are making efforts to find treatment possibilities that modify the disease course or alleviate disease symptoms. Since neuroimaging studies in mutation carrying individuals suggest that in nervous system dysfunction begins many years before the onset of any detectable symptoms, the development of therapeutic interventions becomes of great importance, not only to slow progression of manifest disease but also to delay, or ideally prevent, its onset. Potential therapeutic targets for MJD and polyQ diseases can be divided into (i) those that are aimed at the polyQ proteins themselves, namely gene silencing, attempts to enhance mutant protein degradation or inhibition/prevention of aggregation; and (ii) those that intercept the toxic downstream effects of the polyQ proteins, such as mitochondrial dysfunction and oxidative stress, transcriptional abnormalities, UPS impairment, excitotoxicity, or activation of cell death. The existence of relevant animal models and the recent contributions towards the identification of putative molecular mechanisms underlying MJD are impacting on the development of new drugs. To date only a few preclinical trials were conducted, nevertheless some had very promising results and some candidate drugs are close to being tested in humans. Clinical trials for MJD are also very few to date and their results not very promising, mostly due to trial design constraints. Here, we provide an overview of the pharmacological therapeutic strategies for MJD studied in animal models and patients, and of their possible translation into the clinical practice.