Dissertation

Evaluating the Glycogenic Activity and Therapeutic Capacity of PPP1R3D in a Mouse Model of Lafora Disease

Israelian, Lori

2018

Overview

Lafora disease (LD) is an intractable, neurodegenerative epilepsy caused by loss-of-function mutations in the EPM2A or EPM2B genes. Central to LD is the accumulation of malstructured glycogen (Lafora bodies; LB) in neurons, a consequence of dysregulated glycogen synthesis. Glycogen synthase catalyzes glycogen formation and is activated by dephosphorylation. The latter is mediated by glycogen-targeting subunits of protein phosphatase 1, including PTG (R5) and R6, known formally as PPP1R3D, both abundantly expressed in brain. PTG knockout in LD mice rescues LD, including near-complete disappearance of LB and neurodegeneration. I examined whether the same could be achieved with R6 knockout. Despite significant brain glycogen and LB reductions in R6-deficient-Epm2a-/- mice, substantial amounts of LB remained and neurodegeneration was not rescued. This partial effect remains unexplained. Future experiments to resolve the difference with PTG will shed important light on both LB formation and Lafora disease, and brain glycogen metabolism.

• Publisher: ProQuest Dissertations & Theses
• Subject: Biochemistry / Genetics / Molecular biology
• ISBN: 9780438671034, 0438671031