Abstract
Adult polyglucosan body disease (APBD) is a neurological disorder characterized by adult-onset neurogenic bladder, spasticity, weakness, and sensory loss. The disease is caused by aberrant glycogen branching enzyme (GBE) (GBE1Y329S) yielding less branched, globular, and soluble glycogen, which tends to aggregate. We explore here whether, despite being a soluble enzyme, GBE1 activity is regulated by protein-membrane interactions. Because soluble proteins can contact a wide variety of cell membranes, we investigated the interactions of purified WT and GBE1Y329S proteins with different types of model membranes (liposomes). Interestingly, both triheptanoin and some triacylglycerol mimetics (TGMs) we have designed (TGM0 and TGM5) markedly enhance GBE1Y329S activity, possibly enough for reversing APBD symptoms. We show that the GBE1Y329S mutation exposes a hydrophobic amino acid stretch, which can either stabilize and enhance or alternatively, reduce the enzyme activity via alteration of protein-membrane interactions. Additionally, we found that WT, but not Y329S, GBE1 activity is modulated by Ca2+ and phosphatidylserine, probably associated with GBE1-mediated regulation of energy consumption and storage. The thermal stabilization and increase in GBE1Y329S activity induced by TGM5 and its omega-3 oil structure suggest that this molecule has a considerable therapeutic potential for treating APBD.
Highlights
Adult polyglucosan body disease (APBD) is a neurological disorder characterized by adult-onset neurogenic bladder, spasticity, weakness, and sensory loss
More mutant GBE1Y329S bound to large unilamellar vesicle (LUV) (Fig. 3), suggesting that the internal hydrophobic region flanking Y329S could be exposed at the protein’s surface and become involved in membrane lipid interactions, along with other domains
We investigated the effects of TH and the aforementioned triacylglycerol mimetic (TGM) on the membrane interactions and activity of GBE1 (WT and Y329S)
Summary
Adult polyglucosan body disease (APBD) is a neurological disorder characterized by adult-onset neurogenic bladder, spasticity, weakness, and sensory loss. Inactivation of GBE1 and the activation of glycogen synthase (GYS) leads to the generation of polyglucosan bodies (amylopectin-like polysaccharides with fewer branch points), which are harmful to neurons and glial cells These aggregates may cause different phenotypic alterations, such as neurogenic bladder, partial motor dysfunction in the extremities, sensorial dysfunction in the lower part of the Abbreviations: APBD, adult polyglucosan body disease; Cho, cholesterol; DSC, differential scanning calorimetry; DSF, differential scanning fluorometry; ER, endoplasmic reticulum; GBE, glycogen branching enzyme; GYS, glycogen synthase; IOD, integrated optical density; LUV, large unilamellar vesicle; Ni-NTA, nickel-nitrilotriacetic acid; PBMC, peripheral blood mononuclear cell; PC, phosphatidylcholine; PE, phosphatidylethanolamine; PI[4,5]P2, phosphatidylinositol-4,5-bisphosphate; POPE, 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine; PS, phosphatidylserine; TGM, triacylglycerol mimetic; TH, triheptanoin; Tm, melting temperature
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
