Impaired α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) Receptor Trafficking and Function by Mutant Huntingtin

Mandal, Madhuchhanda; Wei, Jing; Zhong, Ping; Cheng, Jia; Duffney, Lara J.; Liu, Wenhua; Yuen, Eunice Y.; Twelvetrees, Alison E.; Li, Shihua; Li, Shengbo Eben; Kittler, Josef T.; Yan, Zhen

doi:10.1074/jbc.m111.236521

Cited by 53 publications

(40 citation statements)

References 54 publications

(63 reference statements)

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“…For example, Hap1 was originally found to interact with htt, the HD protein (6) that is essential for early embryonic development (44). Later studies showed that mutant htt could affect the intracellular trafficking of various cargos via its avid binding to Hap1 (14,(45)(46)(47)(48)(49)(50). However, the pathological features of HD are age dependent and are characterized by progressive neurodegeneration, suggesting that a gain of toxic function plays a predominant role in HD pathology.…”

Section: Discussionmentioning

confidence: 99%

“…However, after inducing Hap1 depletion in mice via TM injection, we saw none of the typical HD symptoms in adult mice. Because mutant htt affects intracellular trafficking via its abnormal interaction with Hap1 (14,(45)(46)(47)(48)(49)(50), the loss of Hap1 in the absence of mutant htt may be unable to mimic the pathological changes in HD. Rather, the consequences of the loss of Hap1 are more likely to reveal the fundamental function of Hap1.…”

Section: Discussionmentioning

confidence: 99%

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Huntingtin-associated protein 1 regulates postnatal neurogenesis and neurotrophin receptor sorting

Xiang¹,

Yang²,

Zhao³

et al. 2013

J. Clin. Invest.

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Defective neurogenesis in the postnatal brain can lead to many neurological and psychiatric disorders, yet the mechanism behind postnatal neurogenesis remains to be investigated. Huntingtin-associated protein 1 (HAP1) participates in intracellular trafficking in neurons, and its absence leads to postnatal death in mice. Here, we used tamoxifen-induced (TM-induced) Cre recombination to deplete HAP1 in mice at different ages. We found that HAP1 reduction selectively affects survival and growth of postnatal mice, but not adults. Neurogenesis, but not gliogenesis, was affected in HAP1-null neurospheres and mouse brain. In the absence of HAP1, postnatal hypothalamic neurons exhibited reduced receptor tropomyosin-related kinase B (TRKB) levels and decreased survival. HAP1 stabilized the association of TRKB with the intracellular sorting protein sortilin, prevented TRKB degradation, and promoted its anterograde transport. Our findings indicate that intracellular sorting of neurotrophin receptors is critical for postnatal neurogenesis and could provide a therapeutic target for defective postnatal neurogenesis.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Huntingtin-associated protein 1 regulates postnatal neurogenesis and neurotrophin receptor sorting

Xiang¹,

Yang²,

Zhao³

et al. 2013

J. Clin. Invest.

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“…KIF5 also transports glycine receptors by binding to gephyrin Maas et al, 2006). At the same time, KIF5 transports the AMPA receptor subunit GluA2 with HAP1 towards excitatory synapses (Mandal et al, 2011). Therefore, for the inhibitory synaptic targeting of FGF7, gephyrin seems to be the essential component of the transport complex that gives specificity to travel to the inhibitory synapse.…”

Section: Discussionmentioning

confidence: 99%

Selective synaptic targeting of the excitatory and inhibitory presynaptic organizers, FGF22 and FGF7

Terauchi

Timmons

Kikuma

et al. 2014

Journal of Cell Science

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Specific formation of excitatory and inhibitory synapses is crucial for proper functioning of the brain. Fibroblast growth factor 22 (FGF22) and FGF7 are postsynaptic-cell-derived presynaptic organizers necessary for excitatory and inhibitory presynaptic differentiation, respectively, in the hippocampus. For the establishment of specific synaptic networks, these FGFs must localize to appropriate synaptic locations -FGF22 to excitatory and FGF7 to inhibitory postsynaptic sites. Here, we show that distinct motor and adaptor proteins contribute to intracellular microtubule transport of FGF22 and FGF7. Excitatory synaptic targeting of FGF22 requires the motor proteins KIF3A and KIF17 and the adaptor protein SAP102 (also known as DLG3). By contrast, inhibitory synaptic targeting of FGF7 requires the motor KIF5 and the adaptor gephyrin. Time-lapse imaging shows that FGF22 moves with SAP102, whereas FGF7 moves with gephyrin. These results reveal the basis of selective targeting of the excitatory and inhibitory presynaptic organizers that supports their different synaptogenic functions. Finally, we found that knockdown of SAP102 or PSD95 (also known as DLG4), which impairs the differentiation of excitatory synapses, alters FGF7 localization, suggesting that signals from excitatory synapses might regulate inhibitory synapse formation by controlling the distribution of the inhibitory presynaptic organizer.

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“…Kinesin heavy chain has a conserved N-terminal motor domain that is responsible for microtubule binding and a diverse C-terminal non-motor domain containing kinesin light chain binding domain and cargo binding domain. Previous studies by us and others have found that kinesin motor proteins are important for the microtubule-based transport of ionotropic glutamate receptors and the efficacy of excitatory synaptic transmission (34,36,(42)(43)(44)(45). The role of KIF5 motors in regulating GABA A R trafficking and the strength of inhibitory synaptic transmission was later revealed by our studies (27,33).…”

Section: Discussionmentioning

confidence: 54%

“…To test the role of KIF5 in GABA A R trafficking and function, we transfected neurons with the siRNA against KIF5 light chain 1 (KLC1), which caused an effective suppression of KLC1 expression (34). KLCs are essential for the proper function or localization of KIF5 heavy chains (35).…”

Section: Disc1 Knockdown or Overexpressionmentioning

confidence: 99%

DISC1 Protein Regulates γ-Aminobutyric Acid, Type A (GABAA) Receptor Trafficking and Inhibitory Synaptic Transmission in Cortical Neurons

Wei

Graziane

et al. 2015

Journal of Biological Chemistry

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Background:The impact of DISC1, a key protein driving the endophenotypes of major mental disorders, on GABAergic inhibition is unknown. Results: DISC1 knockdown or overexpression altered GABA A R-mediated synaptic transmission by regulating kinesin motor/ microtubule-based GABA A R trafficking. Conclusion: DISC1 exerts an important effect on GABA A R trafficking and synaptic inhibition. Significance: Our observations may be relevant for the role of DISC1 in mental disorders associated with altered GABAergic inhibition.

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Impaired α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) Receptor Trafficking and Function by Mutant Huntingtin

Cited by 53 publications

References 54 publications

Huntingtin-associated protein 1 regulates postnatal neurogenesis and neurotrophin receptor sorting

Huntingtin-associated protein 1 regulates postnatal neurogenesis and neurotrophin receptor sorting

Selective synaptic targeting of the excitatory and inhibitory presynaptic organizers, FGF22 and FGF7

DISC1 Protein Regulates γ-Aminobutyric Acid, Type A (GABAA) Receptor Trafficking and Inhibitory Synaptic Transmission in Cortical Neurons

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