RP6: Degradative routes of intracellular proteins in lysosomal disorders

• Applicant: Professor Dr. Thomas Braulke
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells
• Term: from 2007 to 2013
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 35615435

Defects in the type III membrane proteins CLN6 and GlcNAc-1-phosphotransferase localized in the endoplasmatic reticulum (ER) and the Golgi apparatus, respectively, lead to fatal inherited forms of neurodegenerative lysosomal storage disorders. Whereas the function of CLN6 is unknown, the phosphotransferase catalyzes the key step in the formation of the mannose 6-phosphate (M6P) targeting marker of lysosomal enzymes. Both nclf, Cln6-deficient mice, and our novel phosphotransferase knock-in mice represent models resembling the clinical and biochemical course of the human diseases.In this project we want to investigate the role of lysosomes in the turnover and processing/activation of both endogenous and overexpressed proteins localized in post- ER compartments and in mitochondria of neuronal cells prepared from wild-type, ncIf and phosphotransferase knock-in mice. Pure lysosomal fractions will be analysed to identify accumulating brain proteins in the storage material followed by examination of their neurotoxic potential in the disease-related mouse models. Finally, the M6P-proteome of ncif brain tissues will be analyzed to identify distinct disease-linked changes in M6P-containing proteins. The results are expected to provide insight into the role of lysosomes in intracellular protein degradation and tissue-specific lysosomal functions depending on the composition of M6P-containing lysosomal constituents.

• DFG Programme: Research Units
• Subproject of: FOR 885: Neuronal Protein Turnover