Molecular Pathways and Recent Therapeutic Strategies for Polyglutamine Diseases

The abnormal expansion of trinucleotide cytosine-adenine-guanine [CAG] repeats within disease-associated genes is the primary cause of polyglutamine [polyQ] diseases. This study aims to evaluate the pathological threshold at which the polyglutamine [polyQ] tract, following mutation, leads to neurotoxic effects and to explore emerging therapeutic strategies targeting these mechanisms. The formation of protein aggregates comprising pathogenic polyQ proteins, which induce cellular cytotoxicity, is a key hallmark of polyQ diseases. Despite extensive research, the molecular pathways responsible for the cellular toxicity caused by mutant polyQ proteins remain untreatable. However, strategies to reduce the abnormal expansion of CAG repeats, inhibit the accumulation and aggregation of toxic polyQ-expanded proteins, and promote protein refolding, degradation, or prevention of proteolytic cleavage have shown promise. Additionally, therapeutic approaches such as induced autophagy and stem cell therapies represent promising avenues for intervention. Current treatment modalities for polyQ diseases primarily focus on temporarily alleviating symptoms and slowing disease progression. Continued research into targeted therapeutic strategies is essential to address the underlying pathophysiology of these disorders effectively.