The Roles of Microtubule-Based Transport at Presynaptic Nerve Terminals

Yagensky, Oleksandr; Dehaghi, Tahere Kalantary; Chua, John Jia En

doi:10.3389/fnsyn.2016.00003

Cited by 16 publications

(12 citation statements)

References 108 publications

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“…This latter possibility needs to be further addressed in the case of GFP::RAB-3 vesicles. Retrograde axonal transport allows for synaptic renewal (60), and impairments in this process could contribute to the defective neurotransmission and short-term learning observed in our A152T tau animals. These data, as well as our observation that A152T tau more easily diffuses into somatodendritic compartments (Fig.…”

Section: Discussionmentioning

confidence: 99%

Tau/MAPT disease-associated variant A152T alters tau function and toxicity via impaired retrograde axonal transport

Butler

Salazar

Soriano-Castell

et al. 2018

Human Molecular Genetics

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Mutations in the microtubule-associated protein tau ( MAPT ) underlie multiple neurodegenerative disorders, yet the pathophysiological mechanisms are unclear. A novel variant in MAPT resulting in an alanine to threonine substitution at position 152 (A152T tau) has recently been described as a significant risk factor for both frontotemporal lobar degeneration and Alzheimer’s disease. Here we use complementary computational, biochemical, molecular, genetic and imaging approaches in Caenorhabditis elegans and mouse models to interrogate the effects of the A152T variant on tau function. In silico analysis suggests that a threonine at position 152 of tau confers a new phosphorylation site. This finding is borne out by mass spectrometric survey of A152T tau phosphorylation in C. elegans and mouse. Optical pulse-chase experiments of Dendra2-tau demonstrate that A152T tau and phosphomimetic A152E tau exhibit increased diffusion kinetics and the ability to traverse across the axon initial segment more efficiently than wild-type (WT) tau. A C. elegans model of tauopathy reveals that A152T and A152E tau confer patterns of developmental toxicity distinct from WT tau, likely due to differential effects on retrograde axonal transport. These data support a role for phosphorylation of the variant threonine in A152T tau toxicity and suggest a mechanism involving impaired retrograde axonal transport contributing to human neurodegenerative disease.

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Section: Discussionmentioning

confidence: 99%

Tau/MAPT disease-associated variant A152T alters tau function and toxicity via impaired retrograde axonal transport

Butler

Salazar

Soriano-Castell

et al. 2018

Human Molecular Genetics

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“…The interplay between specific microtubule organization features and different molecular motors will have important implications for the delivery of synaptic cargo to presynapses. Although SVP transport to presynapses is primarily mediated by KIF1A [5], other crucial presynaptic components, including the active zone proteins bassoon and piccolo, are transported by KIF5 motors [47]. Although both KIF1A and KIF5 motors convey cargo to presynaptic sites, the relative efficiency of delivery by these two motors differs greatly.…”

Section: A Platform For Efficiently Matching Supply To Demandmentioning

confidence: 99%

Kinesin-3 Responds to Local Microtubule Dynamics to Target Synaptic Cargo Delivery to the Presynapse

et al. 2019

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Graphical Abstract Highlights d Delivery of synaptic vesicle precursors occurs with high precision d Presynaptic sites are hotspots of dynamic GTP-rich microtubule plus ends d KIF1A binds more weakly to the GTP lattice, rapidly detaching from plus ends d A human KIF1A mutation perturbs lattice sensing and reduces synaptic strength SUMMARYNeurons in the CNS establish thousands of en passant synapses along their axons. Robust neurotransmission depends on the replenishment of synaptic components in a spatially precise manner.Using live-cell microscopy and single-molecule reconstitution assays, we find that the delivery of synaptic vesicle precursors (SVPs) to en passant synapses in hippocampal neurons is specified by an interplay between the kinesin-3 KIF1A motor and presynaptic microtubules. Presynaptic sites are hotspots of dynamic microtubules rich in GTPtubulin. KIF1A binds more weakly to GTP-tubulin than GDP-tubulin and competes with end-binding (EB) proteins for binding to the microtubule plus end. A disease-causing mutation within KIF1A that reduces preferential binding to GDP-versus GTPrich microtubules disrupts SVP delivery and reduces presynaptic release upon neuronal stimulation. Thus, the localized enrichment of dynamic microtubules along the axon specifies a localized unloading zone that ensures the accurate delivery of SVPs, controlling presynaptic strength in hippocampal neurons.

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“…In fact, there is evidence that presynaptic transport vesicles may use different Kinesin family members [ 60 ]. Lastly, evidence suggests that many presynaptic cargos share common vesicles as opposed to each protein using a unique set of vesicles [ 61 , 62 ]. For example, synaptic vesicle proteins are incorporated into synaptic vesicle protein transport vesicles while cytomatrix active zone proteins are associated with piccolo-bassoon transport vesicles.…”

Section: Discussionmentioning

confidence: 99%

Photoreceptor Compartment-Specific TULP1 Interactomes

Ebke

Sinha

Pauer

et al. 2021

IJMS

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Photoreceptors are highly compartmentalized cells with large amounts of proteins synthesized in the inner segment (IS) and transported to the outer segment (OS) and synaptic terminal. Tulp1 is a photoreceptor-specific protein localized to the IS and synapse. In the absence of Tulp1, several OS-specific proteins are mislocalized and synaptic vesicle recycling is impaired. To better understand the involvement of Tulp1 in protein trafficking, our approach in the current study was to physically isolate Tulp1-containing photoreceptor compartments by serial tangential sectioning of retinas and to identify compartment-specific Tulp1 binding partners by immunoprecipitation followed by liquid chromatography tandem mass spectrometry. Our results indicate that Tulp1 has two distinct interactomes. We report the identification of: (1) an IS-specific interaction between Tulp1 and the motor protein Kinesin family member 3a (Kif3a), (2) a synaptic-specific interaction between Tulp1 and the scaffold protein Ribeye, and (3) an interaction between Tulp1 and the cytoskeletal protein microtubule-associated protein 1B (MAP1B) in both compartments. Immunolocalization studies in the wild-type retina indicate that Tulp1 and its binding partners co-localize to their respective compartments. Our observations are compatible with Tulp1 functioning in protein trafficking in multiple photoreceptor compartments, likely as an adapter molecule linking vesicles to molecular motors and the cytoskeletal scaffold.

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The Roles of Microtubule-Based Transport at Presynaptic Nerve Terminals

Cited by 16 publications

References 108 publications

Tau/MAPT disease-associated variant A152T alters tau function and toxicity via impaired retrograde axonal transport

Tau/MAPT disease-associated variant A152T alters tau function and toxicity via impaired retrograde axonal transport

Kinesin-3 Responds to Local Microtubule Dynamics to Target Synaptic Cargo Delivery to the Presynapse

Photoreceptor Compartment-Specific TULP1 Interactomes

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