NMDA Receptor Function and NMDA Receptor-Dependent Phosphorylation of Huntingtin Is Altered by the Endocytic Protein HIP1

Metzler, Martina; Gan, Lu; Wong, Tak Pan; Liu, Lidong; Helm, Jeffrey; Liu, Huan; Georgiou, John; Wang, Yushan; Bissada, Nagat; Cheng, Kuo-Hsing; Roder, John; Wang, Yu Tian; Hayden, Michael R.

doi:10.1523/jneurosci.5175-06.2007

Cited by 39 publications

(43 citation statements)

References 61 publications

(89 reference statements)

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“…Our data are consistent with a role for defective endocytosis as an underlying mechanism in HD (Trushina et al, 2006). Importantly, mouse knock-outs of synaptic and/or htt-interacting proteins such as HIP1 (Ferguson et al, 2000;Metzler et al, 2007;Nystuen et al, 2007) often have neurological phenotypes that may be relevant to HD pathogenesis.…”

supporting

confidence: 87%

Huntingtin-Interacting Protein 1 Influences Worm and Mouse Presynaptic Function and ProtectsCaenorhabditis elegansNeurons against Mutant Polyglutamine Toxicity

Parker¹,

Metzler²,

Georgiou³

et al. 2007

J. Neurosci.

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Huntingtin-interacting protein 1 (HIP1) was identified through its interaction with htt (huntingtin), the Huntington's disease (HD) protein. HIP1 is an endocytic protein that influences transport and function of AMPA and NMDA receptors in the brain. However, little is known about its contribution to neuronal dysfunction in HD.We report that the Caenorhabditis elegans HIP1 homolog hipr-1 modulates presynaptic activity and the abundance of synaptobrevin, a protein involved in synaptic vesicle fusion. Presynaptic function was also altered in hippocampal brain slices of HIP1 Ϫ/Ϫ mice demonstrating delayed recovery from synaptic depression and a reduction in paired-pulse facilitation, a form of presynaptic plasticity. Interestingly, neuronal dysfunction in transgenic nematodes expressing mutant N-terminal huntingtin was specifically enhanced by hipr-1 loss of function. A similar effect was observed with several other mutant proteins that are expressed at the synapse and involved in endocytosis, such as unc-11/AP180, unc-26/synaptojanin, and unc-57/endophilin.Thus, HIP1 is involved in presynaptic nerve terminal activity and modulation of mutant polyglutamine-induced neuronal dysfunction. Moreover, synaptic proteins involved in endocytosis may protect neurons against amino acid homopolymer expansion.

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supporting

confidence: 87%

Huntingtin-Interacting Protein 1 Influences Worm and Mouse Presynaptic Function and ProtectsCaenorhabditis elegansNeurons against Mutant Polyglutamine Toxicity

Parker¹,

Metzler²,

Georgiou³

et al. 2007

J. Neurosci.

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“…10 In a loss-of-function model, mice with targeted mutation in the Hip1 gene developed a neurological phenotype, characterized by failure to thrive, tremor, gait ataxia, and epilepsy. 11 Moreover, Hip1 is crucial for a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptor trafficking in primary hippocampal neurons whose defects are associated with major progressive neurological deficits. 12 Thus, the haploinsufficiency of HIP1 is sufficient to alter neuronal homeostasis predisposing the human brain to epilepsy through a mechanism involving abnormal AMPA and NMDA iGluR trafficking.…”

Section: Patient Wbs166mentioning

confidence: 99%

Smaller and larger deletions of the Williams Beuren syndrome region implicate genes involved in mild facial phenotype, epilepsy and autistic traits

et al. 2013

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syndrome (WBS) is a multisystemic disorder caused by a hemizygous deletion of 1.5 Mb on chromosome 7q11.23 spanning 28 genes. A few patients with larger and smaller WBS deletion have been reported. They show clinical features that vary between isolated SVAS to the full spectrum of WBS phenotype, associated with epilepsy or autism spectrum behavior. Here we describe four patients with atypical WBS 7q11.23 deletions. Two carry B3.5 Mb larger deletion towards the telomere that includes Huntingtin-interacting protein 1 (HIP1) and tyrosine 3-monooxygenase/tryptophan 5-monooxigenase activation protein gamma (YWHAG) genes. Other two carry a shorter deletion of B1.2 Mb at centromeric side that excludes the distal WBS genes BAZ1B and FZD9. Along with previously reported cases, genotype-phenotype correlation in the patients described here further suggests that haploinsufficiency of HIP1 and YWHAG might cause the severe neurological and neuropsychological deficits including epilepsy and autistic traits, and that the preservation of BAZ1B and FZD9 genes may be related to mild facial features and moderate neuropsychological deficits. This report highlights the importance to characterize additional patients with 7q11.23 atypical deletions comparing neuropsychological and clinical features between these individuals to shed light on the pathogenic role of genes within and flanking the WBS region.

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“…For this purpose, we immunoprecipitated and enriched total htt from lysate and determined the level of pS421-htt using a phosphospecific antibody as previously described (Warby et al, 2005;Metzler et al, 2007) and as explained in supplemental Figures 1 and 2 (available at www. jneurosci.org as supplemental material).…”

Section: Yac128 Primary Neurons Show Loss Of Phosphorylation Of Ps421mentioning

confidence: 99%

Phosphorylation of Huntingtin at Ser⁴²¹in YAC128 Neurons Is Associated with Protection of YAC128 Neurons from NMDA-Mediated Excitotoxicity and Is Modulated by PP1 and PP2A

Metzler¹,

Gan²,

Mazarei³

et al. 2010

J. Neurosci.

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YAC transgenic mice expressing poly(Q)-expanded full-length huntingtin (mhtt) recapitulate many behavioral and neuropathological features of Huntington disease (HD).We have previously observed a reduction in phosphorylation of mhtt at S421 in the presence of the mutation for HD. In addition, phosphorylation of normal S421-htt is reduced after excitotoxic stimulation of NMDA receptors (NMDARs). To test whether NMDAR stimulation contributes to reduced pS421-htt levels in HD, we determined phosphorylation of htt at Ser 421 after NMDA-induced excitotoxicity in neurons from YAC128 mice. Here, we report that the total level of pS421-htt is reduced in YAC128 primary neurons after excitotoxic NMDAR stimulation. Similarly, the total level of pS421-htt is reduced in YAC128 transgenic mice after quinolinic acid injection into the striatum. In contrast, loss of phosphorylation of pS421-htt is prevented in YAC mice that never develop clinical or neuropathological features of HD [the caspase 6-resistant YAC128 transgene (C6R)].To gain insight into the mechanisms underlying these findings, we determined that the Ser/Thr protein phosphatases PP1 and PP2A dephosphorylate pS421-htt in situ and after excitotoxic stimulation of NMDARs in neurons. Furthermore, increasing the phosphorylation of htt at S421 by blocking PP1 and PP2A activity protects YAC128 striatal neurons from NMDA-induced cell death. These results, together with the observed modulation of pS421-htt levels by dopamine, the reduced expression of PP1 inhibitor Darpp-32 in the striatum of YAC128 mice, and the reduced phosphorylation of PP1 substrate CreB, point to altered regulation of phosphatase activity in HD and highlight enhancing phosphorylation of htt at S421 as a therapeutic target.

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NMDA Receptor Function and NMDA Receptor-Dependent Phosphorylation of Huntingtin Is Altered by the Endocytic Protein HIP1

Cited by 39 publications

References 61 publications

Huntingtin-Interacting Protein 1 Influences Worm and Mouse Presynaptic Function and ProtectsCaenorhabditis elegansNeurons against Mutant Polyglutamine Toxicity

Huntingtin-Interacting Protein 1 Influences Worm and Mouse Presynaptic Function and ProtectsCaenorhabditis elegansNeurons against Mutant Polyglutamine Toxicity

Smaller and larger deletions of the Williams Beuren syndrome region implicate genes involved in mild facial phenotype, epilepsy and autistic traits

Phosphorylation of Huntingtin at Ser⁴²¹in YAC128 Neurons Is Associated with Protection of YAC128 Neurons from NMDA-Mediated Excitotoxicity and Is Modulated by PP1 and PP2A

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NMDA Receptor Function and NMDA Receptor-Dependent Phosphorylation of Huntingtin Is Altered by the Endocytic Protein HIP1

Cited by 39 publications

References 61 publications

Huntingtin-Interacting Protein 1 Influences Worm and Mouse Presynaptic Function and ProtectsCaenorhabditis elegansNeurons against Mutant Polyglutamine Toxicity

Huntingtin-Interacting Protein 1 Influences Worm and Mouse Presynaptic Function and ProtectsCaenorhabditis elegansNeurons against Mutant Polyglutamine Toxicity

Smaller and larger deletions of the Williams Beuren syndrome region implicate genes involved in mild facial phenotype, epilepsy and autistic traits

Phosphorylation of Huntingtin at Ser421in YAC128 Neurons Is Associated with Protection of YAC128 Neurons from NMDA-Mediated Excitotoxicity and Is Modulated by PP1 and PP2A

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Phosphorylation of Huntingtin at Ser⁴²¹in YAC128 Neurons Is Associated with Protection of YAC128 Neurons from NMDA-Mediated Excitotoxicity and Is Modulated by PP1 and PP2A