Role of the gamma-subunit of the GlcNAc-1-phosphotransferase complex for selective mannose 6-phosphate modifications on lysosomal enzymes

• Applicant: Professorin Dr. Sandra Pohl
• Subject Area: Pediatric and Adolescent Medicine ; Orthopaedics, Traumatology, Reconstructive Surgery
• Term: since 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 395238399

The efficient transport of more than 70 lysosomal enzymes to lysosomes requires mannose 6-phosphate residues (M6P) that are generates by the GlcNAc-1-phosphotransferase in the Golgi appartus. Whereas the alpha- and beta-subunits (GNPTAB) contain the catalytic center, the function of the gamma-subunit (GNPTG) is still largely unknown. Defects in the GNPTAB and GNPTG genes result in the lysosomal storage disorders mucolipidosis type II (MLII) and type III (MLIII), which manifest during early childhood. The intracellular deficiency of missorted lysosomal enzymes result in the accumulation of non-degradaded macromolecules in different tissues. As mainly the skeleton is affected in patients with MLIII specific lysosomal enzymes may play an important role in bone remodeling homeostasis. However, the cellular and molecular mechanisms of the skeletal abnormalities in MLII and MLIII are poorly defined and there are no causal therapy options available so far. Therefore, in this project the pathomechanisms of the MLII and MLIII diseases will be thoroughly studied. The molecular knowledge of the defective protein complex (1), deep insights into the underlying molecular mechanisms of the skeletal pathogenesis (2) are strictly required to establish a treatment option for these diseases.

• DFG Programme: Research Grants