Proteasome function in neurodegenerative disease

Neurodegenerative diseases (NDs), such as Alzheimer’s Disease (AD), represent a significant and growing challenge to global health. These conditions are characterized by the accumulation of pathogenic intrinsically disordered proteins (IDPs) such as tau, α-synuclein, and Amyloid-β. In healthy cells, these proteins are efficiently degraded by the proteasome system, which maintains cellular protein homeostasis (proteostasis). However, in ND, the accumulation of IDPs in oligomeric states and stable aggregates indicates a failure of this crucial cellular machinery. Our research aims to delineate specific pathways of IDP degradation and understand how their disruption contributes to ND pathology. We focus on ubiquitin-independent protein degradation mechanisms, which offer potential therapeutic strategies for enhancing IDP clearance in various NDs before these proteins have a chance to misfold and potentially gain toxic functions. Our preliminary studies in animal models have shown promising results. Activation of the 20S proteasome enhanced IDP degradation and increased organismal longevity and reduced proteotoxic stresses associated with ND, providing a foundation for elucidating the cellular mechanism of this ubiquitin-independent protective pathway. Our research program is organized into three main objectives that investigate the neuroprotective mechanisms of IDP degradation by 3 different ubiquitin- independent pathways for protein degradation catalyzed by the (1) 20S proteasome, the (2) PA200-20S complex, and (3) PA28γ-20S complex. Through this comprehensive approach, we aim to provide detailed insights into these proteasomal pathways' roles in maintaining neuronal health and their influence on the progression in C. elegans models of ND with a focus on AD. Our work has the potential to enhance our understanding of ND pathology and contribute to the development of new treatments targeting the fundamental mechanisms of Alzheimer’s and related neurodegenerative diseases. Project Number: 1R01NS146376-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Neurological Disorders and Stroke (NINDS) | Principal Investigator: David Smith | Institution: WEST VIRGINIA UNIVERSITY, MORGANTOWN, WV | Award Amount: $567,047 | Activity Code: R01 | Study Section: Cellular and Molecular Biology of Neurodegeneration Study Section[CMND] View on NIH RePORTER: https://reporter.nih.gov/project-details/11278435