Prevention of Nuclear Pore Injury in Sporadic and C9orf72 ALS/FTD: Antisense Inhibition of CHMP7
Abstract
Amyotrophic Lateral Sclerosis (ALS) is a devastating and universally fatal neurodegenerative disease. While multiple genetic mutations have been identified as causative of ALS, the vast majority of cases remain sporadic in nature. Additionally, the precise molecular events leading to neurodegeneration in ALS and related diseases remain largely unknown. Defects in an essential cellular process which maintains communication between nuclear and cytoplasmic compartments of the cell (nucleocytoplasmic transport, NCT) have recently emerged as a prominent pathomechanism underlying ALS and other neurodegenerative diseases. The nuclear pore complex (NPC) is made up of multiple copies of approx. 30 individual proteins (Nups) and tightly regulates NCT. However, the mechanisms leading to alterations in NPC composition and function remain understudied. We have now identified a reproducible subset of Nups that are altered as an early event in disease pathogenesis. Moreover, we have determined that these Nups are aberrantly degraded from neuronal NPCs. We now seek to understand the mechanism by which this degradation event is initiated in ALS and related neurodegenerative diseases. In addition, we hope to evaluate the potential of this degradative pathway as a therapeutic target. This work is uniquely poised to both understand the molecular events leading to NPC injury in ALS but also identify new therapeutic targets for the treatment of devastating neurological diseases.
Document Details
- Document Type
- Technical Report
- Publication Date
- Aug 01, 2022
- Accession Number
- AD1190406
Entities
People
- Jeffrey D Rothstein
Organizations
- Johns Hopkins University