Therapeutic strategies for polyQ diseases: from cellular and animal models to the clinic

Abstract

Polyglutamine (PolyQ) diseases are a group of neurodegenerative disorders caused by the expansion of an unstable CAG trinucleotide repeat within the coding region of several otherwise unrelated genes. This expansion encodes an abnormally long polyQ tract that which, above a threshold size, leads to misfolding and aggregation, eventually resulting in neurodegeneration. These disorders all share key features including: (i) dominant transmission; (ii) adult onset; (iii) abnormal protein aggregation; (iv) selective neuronal susceptibility, despite the widespread expression of the disease-related proteins and (v) cellular toxicity that impacts at the organism level. These commonalities point to shared mechanism(s) underlying their pathogenesis. To date, effective therapeutic strategies are still lacking for polyQ diseases although some symptoms can be controlled with specific treatments. Moreover, neuroimaging studies in mutation carrier individuals suggest that nervous system dysfunction begins many years before the onset of any diagnosable symptoms. Thus, 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 polyQ disorders 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; or (ii) those that intercept the toxic downstream effects of the polyQ protein such as mitochondrial dysfunction and oxidative stress, transcriptional abnormalities, UPS impairment, excitotoxicity, or activation of apoptotic pathways. The existence of relevant animal models and the recent contributions towards the identification of putative molecular mechanisms underlying polyQ diseases are impacting on the development of new drugs. Here, we provide an overview of the therapeutic strategies for polyQ disorders in cellular and animal models and their possible translation into the clinics.