Huntingtin recruits KIF1A to transport synaptic vesicle precursors along the mouse axon to support synaptic transmission and motor skill learning
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eLife assessment
In this important study, the authors examine transport and synaptic activity in the corticostriatal circuit in both microfluidic devices and in mice. They convincingly show that the Huntingtin protein regulates the anterograde transport of synaptic vesicle precursors in coordination with the molecular motor KIF1A. Activated Huntingtin recruits KIF1A, accelerates synaptic vesicle precursor's transport, modifies synaptic transmission and motor skill learning in mice. This work sheds new light on the role of axonal transport in synaptic function under physiological and pathological conditions related to Huntington's disease.
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Abstract
Neurotransmitters are released at synapses by synaptic vesicles (SVs), which originate from SV precursors (SVPs) that have traveled along the axon. Because each synapse maintains a pool of SVs, only a small fraction of which are released, it has been thought that axonal transport of SVPs does not affect synaptic function. Here, studying the corticostriatal network both in microfluidic devices and in mice, we find that phosphorylation of the Huntingtin protein (HTT) increases axonal transport of SVPs and synaptic glutamate release by recruiting the kinesin motor KIF1A. In mice, constitutive HTT phosphorylation causes SV over-accumulation at synapses, increases the probability of SV release, and impairs motor skill learning on the rotating rod. Silencing KIF1A in these mice restored SV transport and motor skill learning to wild-type levels. Axonal SVP transport within the corticostriatal network thus influences synaptic plasticity and motor skill learning.
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eLife assessment
In this important study, the authors examine transport and synaptic activity in the corticostriatal circuit in both microfluidic devices and in mice. They convincingly show that the Huntingtin protein regulates the anterograde transport of synaptic vesicle precursors in coordination with the molecular motor KIF1A. Activated Huntingtin recruits KIF1A, accelerates synaptic vesicle precursor's transport, modifies synaptic transmission and motor skill learning in mice. This work sheds new light on the role of axonal transport in synaptic function under physiological and pathological conditions related to Huntington's disease.
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Reviewer #1 (Public Review):
The manuscript by Vitet et al. reveals the role of the motor adaptor protein Huntingtin in regulating the pool of synaptic vesicles via its phosphorylation and binding to Kinesin-3 motor protein on one end and synaptic vesicle precursors on the other. The authors use both genetic models of mice harboring mutations in the HTT gene that either mimic constitutive phosphorylation of Huntingtin protein or a phospho-dead version of it. Despite previous reports suggesting no functional outcome for these mutations, using modified motor tests, the authors identified that constitutive phosphorylation of huntingtin impairs the motor skill learning of mice. Next, in a set of elegant and multidisciplinary methods, including electrophysiological recordings in acute slices, TEM imaging, knock-out rescue assay, and …
Reviewer #1 (Public Review):
The manuscript by Vitet et al. reveals the role of the motor adaptor protein Huntingtin in regulating the pool of synaptic vesicles via its phosphorylation and binding to Kinesin-3 motor protein on one end and synaptic vesicle precursors on the other. The authors use both genetic models of mice harboring mutations in the HTT gene that either mimic constitutive phosphorylation of Huntingtin protein or a phospho-dead version of it. Despite previous reports suggesting no functional outcome for these mutations, using modified motor tests, the authors identified that constitutive phosphorylation of huntingtin impairs the motor skill learning of mice. Next, in a set of elegant and multidisciplinary methods, including electrophysiological recordings in acute slices, TEM imaging, knock-out rescue assay, and biochemical and in-vitro approaches, the authors suggest the mechanism for this dysfunction is through the accumulation of synaptic vesicles in the constitutive phosphorylation mode of huntingtin which increases the release probability and the corticostriatal network. The authors show that this accumulation is mediated by enhanced interaction between vesicular and phosphorylated huntingtin with Kinesin-3 motor proteins which drives the anterograde transport of synaptic vesicle precursors towards the axons and synaptic terminals.
Altogether, this reviewer finds this manuscript well written, well performed, comprehensive and convincing. The new findings in this work are a fundamental addition to the understanding of both basic mechanisms of neuronal function, as well as their dysfunction in neurodegenerative diseases, in this case, Huntington's disease.
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Reviewer #2 (Public Review):
This work presents valuable evidence of the connection between Huntingtin's (HTT) phosphorylation state and the recruitment of Kif1A in the axonal anterograde trafficking of synaptic vesicles precursors (SVPs). In brief, the authors describe how phosphorylation of HTT in Serine 421 determines the recruitment of the anterograde molecular motor Kif1A to SVPs, increasing their rate of transport along the axons to the synapse. This conclusion is substantiated by the measured impact of HTT phosphorylation on motor skills learning ability.
The study presents a variety of investigative angles, combining both ex vitro and in vivo approaches. The use of custom microfluidics chamber to recreate neuronal circuits is a point of strength as it allows for in depth analysis of the transport phenotype. This tool could be a …
Reviewer #2 (Public Review):
This work presents valuable evidence of the connection between Huntingtin's (HTT) phosphorylation state and the recruitment of Kif1A in the axonal anterograde trafficking of synaptic vesicles precursors (SVPs). In brief, the authors describe how phosphorylation of HTT in Serine 421 determines the recruitment of the anterograde molecular motor Kif1A to SVPs, increasing their rate of transport along the axons to the synapse. This conclusion is substantiated by the measured impact of HTT phosphorylation on motor skills learning ability.
The study presents a variety of investigative angles, combining both ex vitro and in vivo approaches. The use of custom microfluidics chamber to recreate neuronal circuits is a point of strength as it allows for in depth analysis of the transport phenotype. This tool could be a very useful tool for the community to explore for a variety of similar studies. The use of mouse models also adds credibility to the physiological importance of the findings.
The evidence presented supports the claims, though more emphasis could be added to the explanation and mechanisms behind how an increased transport dynamic of SVPs due to HTT phosphorylation, results in a detrimental effect on motor skill learning. This finding is perhaps the most critical as it reiterates the importance of balance in SVPs transport and highlights how the system is finely regulated and sensitive to both down and upregulation. This fine tuning might ensure the presence of the proper quantity of SVs at synapses to guarantee an effective synaptic function.This works adds an important angle to role of HTT phosphorylation, which could open new avenues of treatment for HTT disease based on the manipulation of HTT phosphorylation state.
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