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1.
PLoS Genet ; 20(5): e1011253, 2024 May.
Article En | MEDLINE | ID: mdl-38722918

Synaptic vesicle proteins (SVps) are transported by the motor UNC-104/KIF1A. We show that SVps travel in heterogeneous carriers in C. elegans neuronal processes, with some SVp carriers co-transporting lysosomal proteins (SV-lysosomes). LRK-1/LRRK2 and the clathrin adaptor protein complex AP-3 play a critical role in the sorting of SVps and lysosomal proteins away from each other at the SV-lysosomal intermediate trafficking compartment. Both SVp carriers lacking lysosomal proteins and SV-lysosomes are dependent on the motor UNC-104/KIF1A for their transport. In lrk-1 mutants, both SVp carriers and SV-lysosomes can travel in axons in the absence of UNC-104, suggesting that LRK-1 plays an important role to enable UNC-104 dependent transport of synaptic vesicle proteins. Additionally, LRK-1 acts upstream of the AP-3 complex and regulates its membrane localization. In the absence of the AP-3 complex, the SV-lysosomes become more dependent on the UNC-104-SYD-2/Liprin-α complex for their transport. Therefore, SYD-2 acts to link upstream trafficking events with the transport of SVps likely through its interaction with the motor UNC-104. We further show that the mistrafficking of SVps into the dendrite in lrk-1 and apb-3 mutants depends on SYD-2, likely by regulating the recruitment of the AP-1/UNC-101. SYD-2 acts in concert with AP complexes to ensure polarized trafficking & transport of SVps.


Adaptor Protein Complex 3 , Caenorhabditis elegans Proteins , Caenorhabditis elegans , Lysosomes , Nerve Tissue Proteins , Synaptic Vesicles , Caenorhabditis elegans Proteins/metabolism , Caenorhabditis elegans Proteins/genetics , Animals , Caenorhabditis elegans/genetics , Caenorhabditis elegans/metabolism , Synaptic Vesicles/metabolism , Synaptic Vesicles/genetics , Adaptor Protein Complex 3/metabolism , Adaptor Protein Complex 3/genetics , Lysosomes/metabolism , Lysosomes/genetics , Nerve Tissue Proteins/metabolism , Nerve Tissue Proteins/genetics , Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/genetics , Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/metabolism , Protein Transport , Protein Serine-Threonine Kinases/metabolism , Protein Serine-Threonine Kinases/genetics , Neurons/metabolism , Kinesins/metabolism , Kinesins/genetics , Intracellular Signaling Peptides and Proteins/metabolism , Intracellular Signaling Peptides and Proteins/genetics , Axons/metabolism , Intercellular Signaling Peptides and Proteins
2.
Genetics ; 227(1)2024 May 07.
Article En | MEDLINE | ID: mdl-38467475

Asymmetric transport of cargo across axonal branches is a field of active research. Mechanisms contributing to preferential cargo transport along specific branches in vivo in wild type neurons are poorly understood. We find that anterograde synaptic vesicles preferentially enter the synaptic branch or pause at the branch point in Caenorhabditis elegans Posterior Lateral Mechanosensory neurons. The synaptic vesicle anterograde kinesin motor UNC-104/KIF1A regulates this vesicle behavior at the branch point. Reduced levels of functional UNC-104 cause vesicles to predominantly pause at the branch point and lose their preference for turning into the synaptic branch. SAM-4/Myrlysin, which aids in recruitment/activation of UNC-104 on synaptic vesicles, regulates vesicle behavior at the branch point similar to UNC-104. Increasing the levels of UNC-104 increases the preference of vesicles to go straight toward the asynaptic end. This suggests that the neuron optimizes UNC-104 levels on the cargo surface to maximize the fraction of vesicles entering the branch and minimize the fraction going to the asynaptic end.


Caenorhabditis elegans Proteins , Caenorhabditis elegans , Kinesins , Nerve Tissue Proteins , Synaptic Vesicles , Animals , Synaptic Vesicles/metabolism , Caenorhabditis elegans Proteins/metabolism , Caenorhabditis elegans Proteins/genetics , Caenorhabditis elegans/metabolism , Caenorhabditis elegans/genetics , Kinesins/metabolism , Kinesins/genetics , Neurons/metabolism
3.
bioRxiv ; 2023 Feb 26.
Article En | MEDLINE | ID: mdl-36865111

Synaptic vesicle proteins (SVps) are thought to travel in heterogeneous carriers dependent on the motor UNC-104/KIF1A. In C. elegans neurons, we found that some SVps are transported along with lysosomal proteins by the motor UNC-104/KIF1A. LRK-1/LRRK2 and the clathrin adaptor protein complex AP-3 are critical for the separation of lysosomal proteins from SVp transport carriers. In lrk-1 mutants, both SVp carriers and SVp carriers containing lysosomal proteins are independent of UNC-104, suggesting that LRK-1 plays a key role in ensuring UNC-104-dependent transport of SVps. Additionally, LRK-1 likely acts upstream of the AP-3 complex and regulates the membrane localization of AP-3. The action of AP-3 is necessary for the active zone protein SYD-2/Liprin-α to facilitate the transport of SVp carriers. In the absence of the AP-3 complex, SYD-2/Liprin-α acts with UNC-104 to instead facilitate the transport of SVp carriers containing lysosomal proteins. We further show that the mistrafficking of SVps into the dendrite in lrk-1 and apb-3 mutants depends on SYD-2, likely by regulating the recruitment of the AP-1/UNC-101. We propose that SYD-2 acts in concert with both the AP-1 and AP-3 complexes to ensure polarized trafficking of SVps.

4.
PLoS Genet ; 13(11): e1007100, 2017 Nov.
Article En | MEDLINE | ID: mdl-29145394

JIP3/UNC-16/dSYD is a MAPK-scaffolding protein with roles in protein trafficking. We show that it is present on the Golgi and is necessary for the polarized distribution of synaptic vesicle proteins (SVPs) and dendritic proteins in neurons. UNC-16 excludes Golgi enzymes from SVP transport carriers and facilitates inclusion of specific SVPs into the same transport carrier. The SVP trafficking roles of UNC-16 are mediated through LRK-1, whose localization to the Golgi is reduced in unc-16 animals. UNC-16, through LRK-1, also enables Golgi-localization of the µ-subunit of the AP-1 complex. AP1 regulates the size but not the composition of SVP transport carriers. Additionally, UNC-16 and LRK-1 through the AP-3 complex regulates the composition but not the size of the SVP transport carrier. These early biogenesis steps are essential for dependence on the synaptic vesicle motor, UNC-104 for axonal transport. Our results show that UNC-16 and its downstream effectors, LRK-1 and the AP complexes function at the Golgi and/or post-Golgi compartments to control early steps of SV biogenesis. The UNC-16 dependent steps of exclusion, inclusion and motor recruitment are critical for polarized distribution of neuronal cargo.


Adaptor Proteins, Signal Transducing/metabolism , Caenorhabditis elegans Proteins/metabolism , Synaptic Vesicles/metabolism , Adaptor Proteins, Signal Transducing/genetics , Animals , Axonal Transport , Caenorhabditis elegans/metabolism , Caenorhabditis elegans Proteins/genetics , Carrier Proteins/metabolism , Dendrites/metabolism , Golgi Apparatus/metabolism , Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/genetics , Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/metabolism , Neurons/metabolism , Protein Serine-Threonine Kinases/genetics , Protein Serine-Threonine Kinases/metabolism , Protein Transport/genetics , Synaptic Vesicles/genetics , Transcription Factor AP-1/metabolism
5.
Front Cell Neurosci ; 10: 26, 2016.
Article En | MEDLINE | ID: mdl-26903811

[This corrects the article on p. 343 in vol. 9, PMID: 26441521.].

6.
Front Cell Neurosci ; 9: 343, 2015.
Article En | MEDLINE | ID: mdl-26441521

Microtubules form important cytoskeletal structures that play a role in establishing and maintaining neuronal polarity, regulating neuronal morphology, transporting cargo, and scaffolding signaling molecules to form signaling hubs. Within a neuronal cell, microtubules are found to have variable lengths and can be both stable and dynamic. Microtubule associated proteins, post-translational modifications of tubulin subunits, microtubule severing enzymes, and signaling molecules are all known to influence both stable and dynamic pools of microtubules. Microtubule dynamics, the process of interconversion between stable and dynamic pools, and the proportions of these two pools have the potential to influence a wide variety of cellular processes. Reduced microtubule stability has been observed in several neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic Lateral Sclerosis (ALS), and tauopathies like Progressive Supranuclear Palsy. Hyperstable microtubules, as seen in Hereditary Spastic Paraplegia (HSP), also lead to neurodegeneration. Therefore, the ratio of stable and dynamic microtubules is likely to be important for neuronal function and perturbation in microtubule dynamics might contribute to disease progression.

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