The Glymphatic System: Novel Biomarker of Disease Severity and Therapeutic Target

Project: Research

Project Details

Project Description

Amyotrophic lateral sclerosis (ALS) is an inexorable condition characterised by the accumulation of hyperphosphorylated and ubiquitinated TDP-43 protein. Recent evidence also points to a prion-like self-propagation of TDP-43 misfolding via the interstitial and cerebrospinal fluids (CSF). As protein aggregation precedes the onset of neurodegeneration, new therapeutic strategies that target the spread of disease across the brain, including eliminating seed proteins and blocking cell-to-cell spread, are of vital importance.
One potential therapeutic target is the glymphatic system; a network of perivascular spaces that becomes highly active during sleep, clearing waste, like TDP-43, from the brain. As sleep is disrupted in ALS, and sleep deprivation results in protein accumulation, we hypothesise that glymphatic function is impaired in ALS.
Using an innovative mouse model of ALS, we will investigate the relationship between sleep, glymphatic clearance, and TDP-43 pathology, and test a novel therapeutic, MK-1064, aimed at improving glymphatic function, to ameliorate TDP-43 pathophysiology.
Effective start/end date1/03/221/03/24