Laforin targets malin to glycogen in Lafora progressive myoclonus epilepsy.
Dis Model Mech
; 16(1)2023 01 01.
Article
in En
| MEDLINE
| ID: mdl-36511140
ABSTRACT
Glycogen is the largest cytosolic macromolecule and is kept in solution through a regular system of short branches allowing hydration. This structure was thought to solely require balanced glycogen synthase and branching enzyme activities. Deposition of overlong branched glycogen in the fatal epilepsy Lafora disease (LD) indicated involvement of the LD gene products laforin and the E3 ubiquitin ligase malin in regulating glycogen structure. Laforin binds glycogen, and LD-causing mutations disrupt this binding, laforin-malin interactions and malin's ligase activity, all indicating a critical role for malin. Neither malin's endogenous function nor location had previously been studied due to lack of suitable antibodies. Here, we generated a mouse in which the native malin gene is tagged with the FLAG sequence. We show that the tagged gene expresses physiologically, malin localizes to glycogen, laforin and malin indeed interact, at glycogen, and malin's presence at glycogen depends on laforin. These results, and mice, open the way to understanding unknown mechanisms of glycogen synthesis critical to LD and potentially other much more common diseases due to incompletely understood defects in glycogen metabolism.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Lafora Disease
/
Ubiquitin-Protein Ligases
/
Protein Tyrosine Phosphatases, Non-Receptor
/
Glycogen
Limits:
Animals
Language:
En
Journal:
Dis Model Mech
Journal subject:
MEDICINA
Year:
2023
Document type:
Article
Affiliation country:
United States