FOR 885:  Neuronal Protein Turnover

• Subject Area: Medicine
• Term: from 2007 to 2013
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 35615435

• Final Report Year: 2015

Final Report Abstract

The Research Unit concentrated on studying neuronal protein turnover under physiological and pathophysiological conditions, specifically investigating 1) molecular pathways involved in neuron-specific protein degradation, 2) contribution of neuronal protein turnover in modulating neuronal excitability, 3) role of impaired neuronal protein homeostasis on neuronal function. The research unit used an interdisciplinary approach bringing together experts from cell biology, biochemistry, molecular biology and neuropathology from Hamburg and from Cologne. Together we showed that specific mechanisms of protein turnover are highly regulated in neurons and the interplay of these mechanisms is essential to maintain neuronal protein homeostasis, the prerequisite for normal brain function. Disturbance of this highly regulated network, be it through ageing mechanisms or through accumulation of misfolded proteins in neurodegenerative disease, can only be compensated for a limited amount of time. Consequences of disturbed neuronal protein turnover are loss of neuronal function and neurodegeneration and follow non-linear dynamics. The data generated by this research unit have contributed to a better understand of the molecular mechanisms underlying dementia and will help in devising strategies to accomplish healthy aging.

Publications

• 3-Hydroxyglutaric acid is transported via the sodium-dependent dicarboxylate transporter NaDC3. J Mol Med. 2007; 85(7): 763-70
  Stellmer F, Keyser B, Burckhardt BC, Koepsell H, Streichert T, Glatzel M, Jabs S, Thiem J, Herdering W, Koeller DM, Goodman SI, Lukacs Z, Ullrich K, Buckhardt G, Braulke T, Mühlhausen C
  
• Accumulation of mutant neuroserpin precedes development of clinical symptoms in familial encephalopathy with neuroserpin inclusion bodies. Am J Pathol. 2007; 170(4):1305-13
  Galliciotti G, Glatzel M, Kinter J, Kozlov SV, Cinelli P, Rülicke T, Sonderegger P
  
• (2008) Accumulation of bis(monoacylglycero)phosphate and gangliosides in mouse models of neuronal ceroid lipofuscinosis. J Neurochem. 106: 1415-1425
  Jabs S, Quitsch A, Käkelä R, Koch B, Tyynelä J, Brade H, Glatzel M, Walkley S, Saftig P, Vanier MT, Braulke T
  
• Transport and distribution of 3-hydoxyglutaric acid before and during induced encephalopathic crises in a mouse model of glutaric aciduria type. Biochim Biophys Acta 2008; 1782(6):385-90
  Keyser B, Glatzel M, Stellmer F, Kortmann B, Lukacs Z, Kölker S, Sauer SW, Muschol N, Herdering W, Thiem J, Goodman SI, Koeller DM, Ullrich K, Braulke T, Mühlhausen C
  
• Dendritic aasembly of heteromeric gamma-aminobutyric acid type B receptor subunits in hippocampal neurons. J Biol Chem. 2009, 8; 284(19):13077-85
  Ramirez OA, Vidal RL, Tello JA, Vargas KJ, Kindler S, Härtel S, Couve A
  
• Shank1 mRNA: Dendritic transport by kinesin and translational control by the 5’untranslated region. Traffic. 2009, 10 (7):844-57
  Fallay K, Schütt J, Iglauer P, Menke K, Maas C, Kneussel M, Kindler S, Wouters FS, Richter D, Kreienkamp HJ
  
• (2010) A novel singlechain antibody fragment for detection of mannose 6-phosphate-containing proteins: application in mucolipidosis type II patients and mice. Am J Pathol. 177:240-247
  Müller-Loennies S, Galliciotti G, Kollmann K, Glatzel M, Braulke T
  
• (2010) Pathogenic mutations cause rapid degradation of lysosomal storage disease-related membrane protein CLN6. Hum Mut . 31: E1163-1174
  Kurze AK, Galliciotti G, Heine C, Mole SE, Quitsch A, Braulke T
  
• Neuroligin 1 is dynamically exchanged at postsynaptic sites. J Neurosci. 2010 Sep 22;30(38):12733-44
  Schapitz IU, Behrend B, Pechmann Y, Lappe-Siefke C, Kneussel SJ, Wallace KE, Stempel AV, Buck F, Grant SG, Schweizer M, Schmitz D, Schwarz JR, Holzbaur EL, Kneussel M
  
• Muskelin regulates actin filament- and microtubule-based GABA(A) receptor transport in neurons. Neuron, Vol. 70. 2011, Issue 1, pp. 66-81.
  Heisler FF, Loebrich S, Pechmann Y, Maier N, Zivkovic AR, Tokito M, Hausrat TJ, Schweizer M, Bähring R, Holzbaur EL, Schmitz D, Kneussel M.
  (See online at https://dx.doi.org/10.1016/j.neuron.2011.03.008)
• (2012) Disruption of the autophagy-lysosome pathway is involved in neuropathology of the nclf mouse model of neuronal ceroid lipofuscinosis. PloS One. 4: e35493
  Thelen M, Damme M, Schweizer M, Hagel C, Wong AMS, Cooper JD, Braulke T, Galliciotti G
  (See online at https://doi.org/10.1371/journal.pone.0035493)
• (2012) High expression of disease-related Cln6 in the cerebral cortex, purkinje cells, dentate gyrus, and hippocampal CA1 neurons. J Neurosci Res. 90: 568-574
  Thelen M, Fehr S, Schweizer M, Braulke T, Galliciotti G
  (See online at https://doi.org/10.1002/jnr.22773)
• (2013) Apoptotic photoreceptor loss and altered expression of lysosomal proteins in the nclf mouse model of neuronal ceroid lipofuscinosis. Invest Ophthalmol Vis Sci 54: 6952-6959
  Bartsch U, Galliciotti G, Jofre GF, Jankowiak W, Hagel C, Braulke T
  (See online at https://doi.org/10.1167/iovs.13-12945)
• A novel interaction between ageing and ER overload in a protein conformational dementia. Genetics, Vol. 193. 2013, no. 3, pp. 865-876.
  Schipanski A., Lange S., Segref A., Gutschmidt A., Lomas D.A., Miranda E., Schweizer M., Hoppe T., Glatzel M.
  (See online at https://doi.org/10.1534/genetics.112.149088)
• Familial Alzheimer’s disease-associated presenilin-1 alters cerebellar activity and calcium homeostasis. Journal of Clinival Investigation, Vol. 124. 2014, Issue 4, pp. 1552-15673.
  Sepulveda-Falla, D., Barrera-Ocampo, A., Hagel, C., Korwitz, A., Vinueza-Veloz, M.F., Zhou, K., Schonewille, M., Zhou, H., Velazquez-Perez, L., Rodriguez-Labrada, R., Villegas, A., Ferrer, I., Lopera, F., Langer, T., De Zeeuw, C.L., Glatzel, M.
  (See online at https://doi.org/10.1172/JCI66407)
• Pathogenesis of human mitochondrial diseases is modulated by reduced activity of the ubiquitin/proteasome system. Cell Metabolism, Vol. 19. 2014, Issue 4, pp. 642-652.
  Segref A., Kevei E., Pokrzywa W., Schmeisser K., Mansfeld J., Livnat-Levanon N., Ensenauer R., Glickman M.H., Ristow M., Hoppe T.
  (See online at https://doi.org/10.1016/j.cmet.2014.01.016)
• New roles of mitochondrial proteases in health and disease. Nature Reviews Molecular Cell Biology, Vol. 16. 2015, pp. 345–359.
  Quirós, P.M., Langer, T.*, Lopez-Otín, C.
  (See online at https://doi.org/10.1038/nrm3984)
• Parkin cooperates with GDNF/Ret signaling to prevent dopaminergic neuron degeneration. Journal of Clinical Investigation, Vol. 125. 2015, Issue 5, pp. 1873-1885.
  Meka DP, Müller-Rischart AK, Nidadavolu P, Mohammadi B, Motori E, Ponna SK, Aboutalebi H, Bassal M, Annamneedi A, Finckh B, Miesbauer M, Rotermund N, Lohr C, Tatzelt J, Winklhofer KF, Kramer ER
  (See online at https://doi.org/10.1172/JCI79300)