Projektdaten

---

Impact of sugar intake on synaptic function during disease and development

---

Glycosylation is the most common post-translational modification of proteins and lipids. Abnormal glycosylation of proteins can induce deleterious effects, which often result in serious malfunctions of different organ systems such as brain and muscle, as observed in AAMR syndrome. AAMR syndrome is characterized by achalasia, alacrima, mental retardation and muscle weakness. It is caused by mutations in GMPPA which encodes for the GDP-mannose-pyrophosphorylase-A (GMPPA). Recently, we identified GMPPA as an allosteric feedback inhibitor of GDP-mannose-pyrophosphorylase-B (GMPPB), which is required to provide GDP-mannose as a sugar donor for glycosylation. Depletion of GMPPA thus results in increased GDP-mannose levels and increases incorporation of mannose into glycochains of various proteins. Homozygous GMPPA KO mice show a progressive gait disorder with muscle weakness. Furthermore, KO mice show cognitive impairments, progressive neurodegeneration and developmental deficits, such as cortical layering defects. Importantly, dietary mannose depletion starting after weaning corrects glycosylation, prevents neurodegeneration and normalizes motor functions as well as skeletal muscle morphology in mice, but does not ameliorate developmental defects. Because several guidance cues for migrating neuronal precursors as well as synaptic proteins are glycosylated, we hypothesize that aberrant glycosylation in GMPPA KO mice during early brain development alters the interaction, localization or stability of glycoproteins involved in cortical development as well as synaptic transmission. Therfore, I propose to study glycosylation and expression of selected guidance molecules during cortical development and to analyze the moleclular mechansims of synaptic transmission in WT and GMPPA KO mice. Furthermore, I will assess if mannose depletion during pregnancy may normalize developmental defects.