Restraint of presynaptic protein levels by Wnd/DLK signaling mediates synaptic defects associated with the kinesin-3 motor Unc-104
Jiaxing Li,
Yao V Zhang,
Elham Asghari Adib,
Doychin T Stanchev,
Xin Xiong,
Susan Klinedinst,
Pushpanjali Soppina,
Thomas Robert Jahn,
Richard I Hume,
Tobias M Rasse,
Catherine A Collins
Affiliations
Jiaxing Li
Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, United States
Yao V Zhang
Junior Research Group Synaptic Plasticity, Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany; Graduate School of Cellular and Molecular Neuroscience, University of Tübingen, Tübingen, Germany
Elham Asghari Adib
Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, United States
Doychin T Stanchev
Junior Research Group Synaptic Plasticity, Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany; Graduate School of Cellular and Molecular Neuroscience, University of Tübingen, Tübingen, Germany
Xin Xiong
Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, United States
Susan Klinedinst
Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, United States
Pushpanjali Soppina
Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, United States
CHS Research Group Proteostasis in Neurodegenerative Disease, DKFZ Deutsches Krebsforschungszentrum, Heidelberg, Germany
Richard I Hume
Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, United States
Tobias M Rasse
Junior Research Group Synaptic Plasticity, Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany; CHS Research Group Proteostasis in Neurodegenerative Disease, DKFZ Deutsches Krebsforschungszentrum, Heidelberg, Germany
The kinesin-3 family member Unc-104/KIF1A is required for axonal transport of many presynaptic components to synapses, and mutation of this gene results in synaptic dysfunction in mice, flies and worms. Our studies at the Drosophila neuromuscular junction indicate that many synaptic defects in unc-104-null mutants are mediated independently of Unc-104’s transport function, via the Wallenda (Wnd)/DLK MAP kinase axonal damage signaling pathway. Wnd signaling becomes activated when Unc-104’s function is disrupted, and leads to impairment of synaptic structure and function by restraining the expression level of active zone (AZ) and synaptic vesicle (SV) components. This action concomitantly suppresses the buildup of synaptic proteins in neuronal cell bodies, hence may play an adaptive role to stresses that impair axonal transport. Wnd signaling also becomes activated when pre-synaptic proteins are over-expressed, suggesting the existence of a feedback circuit to match synaptic protein levels to the transport capacity of the axon.