The roles of intrinsically disordered proteins in neurodegeneration.

Neurodegenerative diseases such as Amyotrophic Lateral Sclerosis, Alzheimer's disease, Parkinson's disease, and Huntington's disease share a common pathological hallmark: the accumulation of misfolded proteins, particularly involving intrinsically disordered proteins (IDPs) like TDP-43, FUS, Tau, α-synuclein, and Huntingtin. These proteins undergo pathological aggregation, forming toxic inclusions that disrupt cellular function. The dysregulation of proteostasis mechanisms, including the ubiquitin-proteasome system (UPS), ubiquitin-independent proteasome system (UIPS), autophagy, and molecular chaperones, exacerbates these proteinopathies by failing to clear misfolded proteins effectively. Emerging therapeutic strategies aim to restore proteostasis through proteasome activators, autophagy enhancers, and chaperone-based interventions to prevent the toxic accumulation of IDPs. Additionally, understanding liquid-liquid phase separation (LLPS) and its role in stress granule dynamics offers novel insights into how aberrant phase transitions contribute to neurodegeneration. By targeting the molecular pathways involved in IDP aggregation and proteostasis regulation, and better understanding the specificity of each component, research in this area will pave the way for innovative therapeutic approaches to combat these neurodegenerative diseases. This review discusses the molecular mechanisms underpinning IDP pathology, highlights recent advancements in drug discovery, and explores the potential of targeting proteostasis machinery to develop effective therapies.