Proteostasis imbalance: Unraveling protein aggregation in neurodegenerative diseases and emerging therapeutic strategies.

Abstract

Neurodegenerative diseases such as Alzheimer's, Parkinson's, Huntington's, and ALS are defined by the accumulation of misfolded and aggregated proteins, which impair cellular function and result in progressive neuronal death. This chapter examines the critical function of proteostasis-cellular protein homeostasis-in sustaining neuronal health and its disruption as a key factor in disease progression. Proteostasis is upheld by a complex array of mechanisms, which encompass molecular chaperones, the ubiquitin-proteasome system, autophagy-lysosomal pathways, and mitochondrial quality control. Impairment of these systems leads to protein misfolding and aggregation, resulting in toxic cellular environments that promote neurodegeneration. Novel therapeutic approaches focus on restoring proteostasis through the enhancement of cellular protein folding, degradation, and clearance mechanisms. This encompasses small molecule chaperones, gene therapy, RNA-based treatments, immunotherapy, autophagy inducers, and stem cell-based approaches, each addressing distinct components of the proteostasis network to mitigate or prevent disease progression. While these therapies show potential, challenges persist, such as possible side effects, selective targeting, and the efficacy of blood-brain barrier penetration. Personalized medicine and combination therapies customized to specific disease profiles are increasingly recognized for their potential to improve efficacy and safety. This chapter consolidates recent developments in therapies aimed at proteostasis, addresses the challenges encountered in clinical applications, and outlines potential future directions for transformative treatments. Ongoing research indicates that proteostasis modulation may significantly alter the course of neurodegenerative disease treatment, potentially enhancing patient outcomes and quality of life.