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.
Highlights
Continual synaptic delivery of biological materials is quintessential for the establishment and maintenance of neurological synapses
To determine if microtubule affinity-regulating kinases (MARKs) phosphorylation of FEZ1 regulates its function in axonal transport, we investigated the effects of loss of MARK function in live Caenorhabditis elegans
We report that FEZ1, a Kinesin-1 adapter involved in neuronal development and axonal transport, is associated with cargoes enriched for presynaptic functions and is regulated by MARK/Par-1, a kinase implicated in the pathogenesis of Alzheimer’s disease
Summary
Continual synaptic delivery of biological materials is quintessential for the establishment and maintenance of neurological synapses. Synaptic delivery of several presynaptic proteins has been shown to involve FEZ1 acting as a Kinesin-1 adapter[18,19] Together, these results suggest that FEZ1 potentially plays a critical role in neuronal development by acting in conjunction with Kinesin-1 to deliver proteins required for neurite outgrowth and synaptic formation or function. Abnormal aggregation of unphosphorylated FEZ1, Kinesin-1 and its putative cargoes is present in the brains of aged wild type and 3XTg-AD mice, a transgenic AD mouse model[20] Taken together, these results provide mechanistic insights into FEZ1’s roles in neuronal development and synaptic function and suggest that impaired delivery of proteins to synapses via a FEZ1-mediated transport route potentially contributes to the pathogenesis observed during Alzheimer’s disease
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
