Nuclear and degradative functions of the ESCRT-III pathway: implications for neurodegenerative disease

The ESCRT machinery plays a pivotal role in membrane-remodeling events across multiple cellular processes including nuclear envelope repair and reformation, nuclear pore complex surveillance, endolysosomal trafficking, and neuronal pruning. Alterations in ESCRT-III functionality have been associated with neurodegenerative diseases including Frontotemporal Dementia (FTD), Amyotrophic Lateral Sclerosis (ALS), and Alzheimer’s Disease (AD). In addition, mutations in specific ESCRT-III proteins have been identified in FTD/ALS. Thus, understanding how disruptions in the fundamental functions of this pathway and its individual protein components in the human central nervous system (CNS) may offer valuable insights into mechanisms underlying neurodegenerative disease pathogenesis and identification of potential therapeutic targets. In this review, we discuss ESCRT components, dynamics, and functions, with a focus on the ESCRT-III pathway. In addition, we explore the implications of altered ESCRT-III function for neurodegeneration with a primary emphasis on nuclear surveillance and endolysosomal trafficking within the CNS.