Regulation of stop codon readthrough of Aqp4 and role in Aβ clearance

2017 Pilot Project Read More

Investigators

Principal Investigator: Joseph Dougherty (WashU Genetics)
Collaborators: John Cirrito (WashU Neurology), Carla Yuede (WashU Neurology)

Description

Alzheimer’s disease is initiated by the accumulation of amyloid-beta aggregates around neurons in the aging brain. A key factor that drives aggregation of amyloid-beta is high concentrations of the peptide. Normally, amyloid-beta is at low levels because it is readily cleared from the brain by several mechanisms including its drainage system (the glymphatic system). This system needs a special water channel (Aqp4) to control fluid flow. We recently found a new form of Aqp4 can be generated in the brain by a process called stop codon readthrough. With Hope Center support, we aim to test whether this new form of Aqp4 can be used to drive better clearance of amyloid-beta in Alzheimer’s test models in order to keep levels low and reduce toxic accumulation. We also aim to identify genes and drugs that can make more of this Aqp4 form in the brain.

Grants and Awards

Neurobiological significance of Aqp4 stop codon readthrough
NIH/NIA 5K99AG061231 (PI, Darshan Sapkota, Cirrito lab)
Public Health Relevance Statement: Project Narrative The concentration of amyloid-β (Aβ) is directly linked to its likelihood to aggregate into toxic species in the Alzheimer’s disease brain. This proposal will determine the role of Aquaporin-4 (Aqp4), particularly an elongated readthrough version of the protein that occurs naturally, in regulating Aβ clearance via astrocytes. Elucidating the mechanisms that regulate Aβ concentration will provide insight into disease pathogenesis as well as risk of disease, and could suggest a new therapeutic target to enhance Aβ clearance from the brain.

Publications

Darshan Sapkota, Allison M. Lake, Wei Yang, Chengran Yang, Hendrik Wesseling, Amanda Guise, Ceren Uncu, Jasbir S. Dalal, Andrew W. Kraft, Jin-Moo Lee, Mark S. Sands, Judith A. Steen, Joseph D. Dougherty. “Cell-Type-Specific Profiling of Alternative Translation Identifies Regulated Protein Isoform Variation in the Mouse Brain”. Cell Reports, Volume 26, Issue 3, 15 January 2019, Pages 594-607.e7

 

Updated April 2021

Investigators

Pilot project teams include Hope Center faculty members and others. For more about Hope Center faculty on this team, click below.

Joseph Dougherty

John Cirrito