Function and regulation of FEZ1, a Kinesin-1 adaptor protein, in transporting presynaptic proteins
Final Report Abstract
Synapses confer neurons with the ability to communicate with each other. This dialogue between neurons forms the essential basis of our cognitive abilities. In particular, synaptic function is conferred by a collection of biological macromolecular complexes that are assembled from hundreds of unique proteins. Many, if not all, of these proteins must be delivered to synapses by intracellular transport complexes. Indeed, synaptic protein transport plays critical roles in the formation and maintenance of synapses and disrupted transport is associated to neurodegenerative disorders such as Alzheimer’s disease and amyotrophic lateral sclerosis. Given such importance, surprisingly little is known about how the transport complexes organize the delivery of synaptic components during synapse formation and maintenance. Here, we show that FEZ1 functions as an integral part of the Kinesin-1 transport complex to deliver key synaptic proteins to synapses. We also identified microtubule affinity regulating kinases (MARKs) as regulators of FEZ1’s role in this process. Prevention of FEZ1 phosphorylation by MARKs causes transport defects in neurons that is connected to the loss and disorganization of synapses. MARKs are a group of kinases involved in the formation of neurofibrillary tangles, a pathological hallmark of Alzheimer’s disease, by hyperphosphorylation of Tau. We determined that aberrant phosphorylation of FEZ1 is also linked to abnormal aggregation of FEZ1 in the brains of 3xTg-AD transgenic mouse. Collectively, these findings indicate that synapse loss, an early and predictive indicator of the onset of AD, can occur as a result of loss of FEZ1 function via abnormal phosphorylation events that disrupt the delivery of key proteins to synapses, thereby impairing their function. Our findings has been highlighted by ALZFORUM (https://www.alzforum.org/papers/phosphorylationfez1-microtubule-affinity-regulating-kinases-regulates-its-function).
Publications
- (2016) Functions of Rab Proteins at Presynaptic Sites. Cells 5
Binotti B, Jahn R, and Chua JJ
(See online at https://doi.org/10.3390/cells5010007) - (2016) Phosphorylation of FEZ1 by Microtubule Affinity Regulating Kinases regulates its function in presynaptic protein trafficking. Scientific reports 6, 26965
Butkevich E, Hartig W, Nikolov M, Erck C, Grosche J, Urlaub H, Schmidt CF, Klopfenstein DR, and Chua JJ
(See online at https://doi.org/10.1038/srep26965) - (2016) The Roles of Microtubule-Based Transport at Presynaptic Nerve Terminals. Frontiers in synaptic neuroscience 8, 3
Yagensky O, Kalantary Dehaghi T, and Chua JJ
(See online at https://doi.org/10.3389/fnsyn.2016.00003)
