Journal of Glycobiology
Open Access

Defects in GlcNAc-1-phosphotransferase cause bone loss, dental abnormalities and B-cell functions

2^nd Glycobiology World Congress

August 29-31, 2016 Atlanta, USA

Thomas Braulke

University Medical Center Hamburg-Eppendorf, Germany

Posters & Accepted Abstracts: J Glycobiol

Abstract :

GlcNAc-1-phosphotransferase (PT) modifies newly synthesized lysosomal enzymes with mannose 6-phosphate (M6P) recognition markers which are required for their efficient targeting to lysosomes. The lack of PT activity lead to mucolipidosis II (MLII) characterized by missorting of multiple lysosomal hydrolases and the accumulation of non-degraded material in lysosomes. To investigate pathomechanisms underlying MLII, we generated a knock-in mouse that mimics clinical (e.g., reduced body length, severe skeletal abnormalities with shortened bones, spine deformity and facial dysmorphism) and biochemical symptoms of MLII patients. The progressive bone loss in MLII was demonstrated to be due to the presence of dysfunctional bone-forming osteoblasts combined with excessive osteoclastogenesis. Although the lysosomal enzymes cathepsin K and the acid phosphatase Acp5 which comprise essential components of bone-resorbing osteoclasts are hyper secreted, MLII osteoclasts are not functionally impaired. Correlative light and electron microscopy suggested that M6P-lacking cathepsin K was secreted basolaterally rather than into the resorption lacuna. Analysis of postnatal tooth development by micro-computed tomography imaging and histology revealed normal dentin and enamel formation and increased cementum thickness accompanied with accumulation of storage material in cementoblasts of MLII mice. Moreover, we observed variable targeting efficiencies of lysosomal enzymes in cells of the immune system in MLII mice which impaired in particular antigen fragmentation and presentation in B-cells maturation and the subsequent immune status whereas T-cells and dendritic cells maintained almost normal functions. Together, the inability to form Man6P residues results in lysosomal dysfunction, accumulation of variable storage material and impaired lysosomal-targeting in an enzyme and cell-dependent manner.

Biography :

Email: braulke@uke.uni-hamburg.de