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

ABSTRACT

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.

KEYWORDS:

• Amyotrophic lateral sclerosis
• endolysosomal trafficking
• ESCRT-III pathway
• frontotemporal dementia
• neurodegenerative diseases
• nuclear pore complex
• nuclear surveillance
• protein degradation

Acknowledgments

We thank America Chandia Cristi and Ssu-Ying Chen for feedback on this manuscript.

Disclosure statement

ANC has submitted patents on methods and drugs to modulate various ESCRT-III proteins in neurodegeneration.

Author contributions

ANC wrote and edited the manuscript. OK carried out all manuscript revisions and assisted with final editing. ANC conceptualized and generated figures. Conceptualization and oversight were carried out by ANC. All authors reviewed and approved the final manuscript.

Data availability statement

Data sharing is not applicable to this article as no new data were created or analyzed in this study.

Additional information

Funding

ANC is supported by funding from NIH NINDS/NIA (R00NS123242), NIH NINDS (R01NS132836), The Robert Packard Center for ALS Research, BrightFocus Foundation, Muscular Dystrophy Association, and Target ALS (IL-2023-C6-L4 and IL-2023-C5-L3).