title: Phosphorylation of FEZ1 by Microtubule Affinity Regulating Kinases regulates its function in presynaptic protein trafficking.
abstract: Adapters bind motor proteins to cargoes and therefore play essential roles in Kinesin-1 mediated intracellular transport. The regulatory mechanisms governing adapter functions and the spectrum of cargoes recognized by individual adapters remain poorly defined. Here, we show that cargoes transported by the Kinesin-1 adapter FEZ1 are enriched for presynaptic components and identify that specific phosphorylation of FEZ1 at its serine 58 regulatory site is mediated by microtubule affinity-regulating kinases (MARK/PAR-1). Loss of MARK/PAR-1 impairs axonal transport, with adapter and cargo abnormally co-aggregating in neuronal cell bodies and axons. Presynaptic specializations are markedly reduced and distorted in FEZ1 and MARK/PAR-1 mutants. Strikingly, abnormal co-aggregates of unphosphorylated FEZ1, Kinesin-1 and its putative cargoes are present in brains of transgenic mice modelling aspects of Alzheimer's disease, a neurodegenerative disorder exhibiting impaired axonal transport and altered MARK activity. Our findings suggest that perturbed FEZ1-mediated synaptic delivery of proteins arising from abnormal signalling potentially contributes to the process of neurodegeneration.
authors.affiliation: Third Institute of Physics-Biophysics, Georg August University Göttingen, 37077, Göttingen, Germany.
authors.forename: Eugenia
authors.initials: E
authors.lastname: Butkevich
authors.affiliation: Paul Flechsig Institute for Brain Research, University of Leipzig, 04103, Leipzig, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Härtig
authors.affiliation: Bioanalytical Mass Spectrometry, Max Planck Institute for Biophysical Chemistry, 37077, Göttingen, Germany.
authors.forename: Miroslav
authors.initials: M
authors.lastname: Nikolov
authors.affiliation: Synaptic Systems, 37079, Göttingen, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Erck
authors.affiliation: Effigos AG, 04103, Leipzig, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Grosche
authors.affiliation: Bioanalytical Mass Spectrometry, Max Planck Institute for Biophysical Chemistry, 37077, Göttingen, Germany.|Bioanalytics, Department of Clinical Chemistry, University Medical Center Göttingen, 37075 Göttingen, Germany.
authors.forename: Henning
authors.initials: H
authors.lastname: Urlaub
authors.affiliation: Third Institute of Physics-Biophysics, Georg August University Göttingen, 37077, Göttingen, Germany.
authors.forename: Christoph F
authors.initials: CF
authors.lastname: Schmidt
authors.affiliation: Third Institute of Physics-Biophysics, Georg August University Göttingen, 37077, Göttingen, Germany.
authors.forename: Dieter R
authors.initials: DR
authors.lastname: Klopfenstein
authors.affiliation: Research Group in Protein Trafficking in Synaptic Development and Function, Department of Neurobiology, Max Planck Institute for Biophysical Chemistry, 37077 Göttingen, Germany.|Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore.|Neurobiology/Ageing Programme, Centre for Life Sciences, National University of Singapore.
authors.forename: John Jia En
authors.initials: JJ
authors.lastname: Chua
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D001370:Axonal Transport / Q000235:genetics*; D017173:Caenorhabditis elegans; D029742:Caenorhabditis elegans Proteins / Q000235:genetics*; D002540:Cerebral Cortex / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006367:HeLa Cells; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D006801:Humans; D016547:Kinesins / Q000235:genetics; D051379:Mice; D009154:Mutation; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics*; D051381:Rats; D009435:Synaptic Transmission; D013572:Synaptic Vesicles / Q000378:metabolism* / Q000473:pathology; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000235:genetics*
chemical_list: D029742:Caenorhabditis elegans Proteins; C574993:Lzts1 protein, mouse; D025521:Tumor Suppressor Proteins; C409406:PAR-1 protein, C elegans; C000623348:F2r protein, rat; C531338:MARK1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D016547:Kinesins