Delivery of GABAARs to Synapses Is Mediated by HAP1-KIF5 and Disrupted by Mutant Huntingtin

Twelvetrees, Alison E.; Yuen, Eunice Y.; Arancibia-Cárcamo, I. Lorena; MacAskill, Andrew F.; Rostaing, Philippe; Lumb, M.; Humbert, Sandrine; Triller, Antoine; Saudou, Frédéric; Yan, Zhen; Kittler, Josef T.

doi:10.1016/j.neuron.2009.12.007

Cited by 224 publications

(261 citation statements)

References 46 publications

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“…We specifically focused on Kif5C and Kif3A kinesin complexes and have identified several proteins that are potentially targeted to synapses. Previous studies identified some cargos of Kif5C, including GABA receptors (22), axonal synaptic vesicle precursors (23), APP-containing vesicles (24,25), TrkB vesicles (26), mitochondria (23,(27)(28)(29)(30)(31), AMPAR vesicles (32), and mRNA/protein complexes (33,34). Kif3 was shown to transport fodrin-associating vesicles in cultured superior cervical ganglion neurons (35), Ncadherin in the developing mouse brain (36) and axonal voltagegated potassium channel in cultured hippocampal neurons (37).…”

Section: Discussionmentioning

confidence: 99%

New approach to capture and characterize synaptic proteome

Liu¹,

Kadakkuzha²,

Pascal³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Little is known regarding the identity of the population of proteins that are transported and localized to synapses. Here we describe a new approach that involves the isolation and systematic proteomic characterization of molecular motor kinesins to identify the populations of proteins transported to synapses. We used this approach to identify and compare proteins transported to synapses by kinesin (Kif) complexes Kif5C and Kif3A in the mouse hippocampus and prefrontal cortex. Approximately 40-50% of the protein cargos identified in our proteomics analysis of kinesin complexes are known synaptic proteins. We also found that the identity of kinesins and where they are expressed determine what proteins they transport. Our results reveal a previously unappreciated role of kinesins in regulating the composition of synaptic proteome.kinesin | protein transport | synapse | proteome | hippocampus

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Section: Discussionmentioning

confidence: 99%

New approach to capture and characterize synaptic proteome

Liu¹,

Kadakkuzha²,

Pascal³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…Rat hippocampal neurons were prepared and cultured from embryonic day 18 rat brains. Cells were transfected by Amaxa nucleofection as previously described (35). See SI Materials and Methods.…”

Section: Methodsmentioning

confidence: 99%

NMDA receptors regulate GABA _A receptor lateral mobility and clustering at inhibitory synapses through serine 327 on the γ2 subunit

Muir¹,

Arancibia-Cárcamo²,

MacAskill³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Modification of the number of GABA A receptors (GABA A Rs) clustered at inhibitory synapses can regulate inhibitory synapse strength with important implications for information processing and nervous system plasticity and pathology. Currently, however, the mechanisms that regulate the number of GABA A Rs at synapses remain poorly understood. By imaging superecliptic pHluorin tagged GABA A R subunits we show that synaptic GABA A R clusters are normally stable, but that increased neuronal activity upon glutamate receptor (GluR) activation results in their rapid and reversible dispersal. This dispersal correlates with increases in the mobility of single GABA A Rs within the clusters as determined using singleparticle tracking of GABA A Rs labeled with quantum dots. GluRdependent dispersal of GABA A R clusters requires Ca 2+ influx via NMDA receptors (NMDARs) and activation of the phosphatase calcineurin. Moreover, the dispersal of GABA A R clusters and increased mobility of individual GABA A Rs are dependent on serine 327 within the intracellular loop of the GABA A R γ2 subunit. Thus, NMDAR signaling, via calcineurin and a key GABA A R phosphorylation site, controls the stability of synaptic GABA A Rs, with important implications for activitydependent control of synaptic inhibition and neuronal plasticity.ion channels | plasticity | trafficking | diffusion | calcineurin S ynaptic inhibition plays a critical role in regulating neuronal excitability and information processing in the brain. The number of GABA A receptors (GABA A Rs) in the surface membrane and at synaptic sites is an important determinant of inhibitory synapse strength (1), but the mechanisms that rapidly control synaptic GABA A R number and stability remain poorly understood. Activation of Ca 2+ -permeable ionotropic glutamate receptors (GluRs) during plasticity and in pathology can result in down-modulation of inhibitory synapse strength and GABA A R function (2-5) but the molecular and cellular mechanisms underlying GluR-dependent changes in the strength of GABAergic inhibition remain unclear.A major mechanism for modulating GABA A R activity is the direct phosphorylation of residues within the intracellular loops of GABA A R subunits, which can regulate synaptic inhibition, GABA A R channel kinetics, and trafficking (6-9). The rapid movement of neurotransmitter receptors (including GABA A Rs) (10-12) into and out of synapses has also recently emerged as an important mechanism for regulating synaptic strength (13). However, whether GABA A R phosphorylation can directly regulate the synaptic stability of GABA A Rs and their lateral diffusion and movement into and out of synapses is unknown.Here, by live cell imaging of surface GABA A R clusters with pHsensitive superecliptic pHluorin (SEP) and single GABA A Rs with quantum dots (QDs), we investigate the mechanisms that regulate activity-dependent control of the lateral diffusion, clustering, and stability of GABA A Rs at inhibitory synapses. We find that Ca 2+ entry through NMDA receptors (NMDARs) l...

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“…Autophagosome transport is regulated by huntingtin (Wong and Holzbaur, 2014a), a scaffolding protein that binds dynein directly (Caviston et al, 2007) and also interacts with dynactin (p150 Glued subunit) and kinesin through Huntingtin-associated protein 1 (HAP-1) (Engelender et al, 1997;Li et al, 1995;Li et al, 1998;McGuire et al, 2006;Twelvetrees et al, 2010). Huntingtin localizes to the outer membrane of autophagosomes (Atwal et al, 2007;Martinez-Vicente et al, 2010) and regulates autophagosome transport through its interactions with dynein and HAP-1 (Wong and Holzbaur, 2014a).…”

Section: Box 2 Regulation Of the Axonal Transport Of Autophagosomesmentioning

confidence: 99%

Autophagosome dynamics in neurodegeneration at a glance

Wong

Holzbaur

2015

Journal of Cell Science

113

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Autophagy is an essential homeostatic process for degrading cellular cargo. Aging organelles and protein aggregates are degraded by the autophagosome-lysosome pathway, which is particularly crucial in neurons. There is increasing evidence implicating defective autophagy in neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), Alzheimer's disease, Parkinson's disease and Huntington's disease. Recent work using live-cell imaging has identified autophagy as a predominantly polarized process in neuronal axons; autophagosomes preferentially form at the axon tip and undergo retrograde transport back towards the cell body. Autophagosomes engulf cargo including damaged mitochondria (mitophagy) and protein aggregates, and subsequently fuse with lysosomes during axonal transport to effectively degrade their internalized cargo. In this Cell Science at a Glance article and the accompanying poster, we review recent progress on the dynamics of the autophagy pathway in neurons and highlight the defects observed at each step of this pathway during neurodegeneration.

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Delivery of GABAARs to Synapses Is Mediated by HAP1-KIF5 and Disrupted by Mutant Huntingtin

Cited by 224 publications

References 46 publications

New approach to capture and characterize synaptic proteome

New approach to capture and characterize synaptic proteome

NMDA receptors regulate GABA _A receptor lateral mobility and clustering at inhibitory synapses through serine 327 on the γ2 subunit

Autophagosome dynamics in neurodegeneration at a glance

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Delivery of GABAARs to Synapses Is Mediated by HAP1-KIF5 and Disrupted by Mutant Huntingtin

Cited by 224 publications

References 46 publications

New approach to capture and characterize synaptic proteome

New approach to capture and characterize synaptic proteome

NMDA receptors regulate GABA A receptor lateral mobility and clustering at inhibitory synapses through serine 327 on the γ2 subunit

Autophagosome dynamics in neurodegeneration at a glance

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NMDA receptors regulate GABA _A receptor lateral mobility and clustering at inhibitory synapses through serine 327 on the γ2 subunit