Mechanistic Insights and Potential Therapeutic Approaches in PolyQ Diseases via Autophagy

Abstract

Polyglutamine diseases are a group of congenital neurodegenerative diseases categorized with genomic abnormalities in the expansion of CAG triplet repeats in coding regions of specific disease-related genes. Protein aggregates are the toxic hallmark for polyQ diseases and initiate neuronal death. Autophagy is a catabolic process that aids in the removal of damaged organelles or toxic protein aggregates, a process required to maintain cellular homeostasis that has the potential to fight against neurodegenerative diseases, but this pathway gets affected under diseased conditions, as there is a direct impact on autophagy-related gene expression. The increase in the accumulation of autophagy vesicles reported in neurodegenerative diseases was due to an increase in autophagy or may have been due to a decrease in autophagy flux. These reports suggested that there is a contribution of autophagy in the pathology of diseases and regulation in the process of autophagy. It was demonstrated in various disease models of polyQ diseases that autophagy upregulation by using modulators can enhance the dissolution of toxic aggregates and delay disease progression. In this review, interaction of the autophagy pathway with polyQ diseases was analyzed, and a therapeutic approach with autophagy inducing drugs was established for disease pathogenesis.

Reviewing the Structure–Function Paradigm in Polyglutamine Disorders: A Synergistic Perspective on Theoretical and Experimental Approaches

“…All these considered, the review paper of Jain M. et al [ 299 ] specifically focuses on the role of autophagy, via highlighting the potential of targeting autophagy pathways as a therapeutic strategy. This approach includes modulation of autophagic activity to manage the accumulation and toxicity of protein aggregates, while offering a promising avenue for treatment development in these neurodegenerative disorders.…”

“…Additionally, the therapeutic effects and modes of action of the available autophagic modulators in polyQ diseases are also provided. Nevertheless, further understanding of autophagy pathways is required, which may lead to multitarget approaches against toxic polyQ strands and neuronal degeneration—with the potential of significantly delaying diseases progression [ 299 ].…”

Polyglutamine (PolyQ) Diseases: Navigating the Landscape of Neurodegeneration

“…Drugs explored in pharmacological treatments of polyQ diseases[147][148][149][150][151][152][153][154] …”