HIP1, a human homologue of S. cerevisiae Sla2p, interacts with membrane-associated huntingtin in the brain

Ma, Kalchman; Hb, Koide; McCutcheon, Krista; Rk, Graham; Nichol, K.; Nishiyama, Kazutoshi; Kazemi-Esfarjani, Parsa; Lynn, Francis C.; Wellington, Cheryll; Metzler, Martina; Yp, Goldberg; Kanazawa, Ichiro; Rd, Gietz; Hayden, Michael R.

doi:10.1038/ng0597-44

Cited by 347 publications

(276 citation statements)

References 45 publications

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“…Although there is some controversy about the role of htt aggregates, many authors propose, on the basis that Htt interacts with proteins associated to cytoskeleton-based transport (Li et al 1995;Kalchman et al 1997;Wanker et al 1997;Li et al 1998), that their presence in the neuropil is implicated in disturbances of axonal transport (Li et al 2001). Our present findings show that decreasing BDNF expression in the R6/1 mouse line increases the number of non-nuclear aggregates, which could be related to the enhanced dysfunction of dopaminergic neurons in bDM mice.…”

Section: Discussionsupporting

confidence: 54%

Brain‐derived neurotrophic factor modulates dopaminergic deficits in a transgenic mouse model of Huntington's disease

Pineda¹,

Canals²,

Bosch³

et al. 2005

Journal of Neurochemistry

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Dysfunction of dopaminergic neurons may contribute to motor impairment in Huntington's disease. Here, we study the role of brain-derived neurotrophic factor (BDNF) in alterations of the nigrostriatal system associated with transgenics carrying mutant huntingtin. Using huntingtin-BDNF +/-double-mutant mice, we analyzed the effects of reducing the levels of BDNF expression in a model of Huntington's disease (R6/1). When compared with R6/1 mice, these mice exhibit an increased number of aggregates in the substantia nigra pars compacta. In addition, reduction of BDNF expression exacerbates the dopaminergic neuronal dysfunction seen in mutant huntingtin mice, such as the decrease in retrograde labelling of dopaminergic neurons and striatal dopamine content. However, mutant huntingtin mice with normal or lowered BDNF expression show the same decrease in the anterograde transport, number of dopaminergic neurons and nigral volume. In addition, reduced BDNF expression causes decreased dopamine receptor expression in mutant huntingtin mice. Examination of changes in locomotor activity induced by dopamine receptor agonists revealed that, in comparison with R6/1 mice, the double mutant mice exhibit lower activity in response to amphetamine, but not to apomorphine. In conclusion, these findings demonstrate that the decreased BDNF expression observed in Huntington's disease exacerbates dopaminergic neuronal dysfunction, which may participate in the motor disturbances associated with this neurodegenerative disorder. Keywords: amphetamine, axonal transport, movement disorders, neuronal dysfunction, neurotrophins, substantia nigra. J. Neurochem. (2005Neurochem. ( ) 93, 1057Neurochem. ( -1068 Neurodegenerative disorders are characterized by a progressive and specific loss of neurons. Huntington's disease (HD) is an autosomal dominant inherited neurodegenerative disorder caused by unstable expanded CAG repeats in the 5¢-coding region of the huntingtin (htt) gene (The Huntington's Disease Collaborative Research Group 1993). The primary brain region affected in HD is the striatum, where a selective degeneration of GABAergic projection neurons occurs. However, neuronal degeneration also extends to other brain areas, including the cerebral cortex, substantia nigra (SN), globus pallidus and subthalamic nucleus as the disease progresses (Rubinsztein 2002;Browne and Beal 2004).The important role of the SN dopaminergic system in the control of motor function suggests that dysfunctional dopaminergic transmission may play a role in motor disturbances, the most common feature of HD (Hickey et al. 2002). In fact, reduced expression of dopamine receptors and Received August 6, 2004; revised manuscript received December 10, 2004; accepted December 14, 2004. Address correspondence and reprint requests to Dr J. Alberch, Departament de Biologia CelAElular i Anatomia Patològica, Facultat de Medicina, Universitat de Barcelona, C/Casanova, 143 E-08036 Barcelona, Spain. E-mail: alberch@ub.eduAbbreviations used: BDA, biotinylated dextran am...

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Section: Discussionsupporting

confidence: 54%

Brain‐derived neurotrophic factor modulates dopaminergic deficits in a transgenic mouse model of Huntington's disease

Pineda¹,

Canals²,

Bosch³

et al. 2005

Journal of Neurochemistry

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“…[12][13][14][15][16] In several cases, the strength of Htt protein interactions has been shown to be affected by the length of polyQ tract, including the interaction with CREB binding protein, 7,9 HAP-1, 17 nuclear receptor co-repressor N-CoR, 18 Sp1 19 and others. 20,21 Rhes, a striatal-specific guanine nucleotide-binding protein, interacts preferentially with polyQ-expanded Htt and induces its sumoylation, leading to cytotoxicity.…”

Section: Resultsmentioning

confidence: 99%

Huntingtin protein interactions altered by polyglutamine expansion as determined by quantitative proteomic analysis

et al. 2012

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“…The 110 kDa protein HIP1, for example, binds to Huntingtin, which suffers poly-glutamine expansions in Huntington's disease. 29,30 Recently, it has been suggested that mutated Huntingtin releases the HIP1 protein, which then is free to interact with another novel protein, Hippi. HIP1 and Hippi reportedly form a complex together with pro-Caspase-8, thereby triggering caspase activation and cell death.…”

Section: Discussionmentioning

confidence: 99%

Bifunctional apoptosis inhibitor (BAR) protects neurons from diverse cell death pathways

et al. 2003

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The bifunctional apoptosis regulator (BAR) is a multidomain protein that was originally identified as an inhibitor of Baxinduced apoptosis. Immunoblot analysis of normal human tissues demonstrated high BAR expression in the brain, compared to low or absent expression in other organs. Immunohistochemical staining of human adult tissues revealed that the BAR protein is predominantly expressed by neurons in the central nervous system. Immunofluorescence microscopy indicated that BAR localizes mainly to the endoplasmic reticulum (ER) of cells. Overexpression of BAR in CSM 14.1 neuronal cells resulted in significant protection from a broad range of cell death stimuli, including agents that activate apoptotic pathways involving mitochondria, TNFfamily death receptors, and ER stress. Downregulation of BAR by antisense oligonucleotides sensitized neuronal cells to induction of apoptosis. Moreover, the search for novel interaction partners of BAR identified several candidate proteins that might contribute to the regulation of neuronal apoptosis (HIP1, Hippi, and Bap31). Taken together, the expression pattern and functional data suggest that the BAR protein is involved in the regulation of neuronal survival.

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HIP1, a human homologue of S. cerevisiae Sla2p, interacts with membrane-associated huntingtin in the brain

Cited by 347 publications

References 45 publications

Brain‐derived neurotrophic factor modulates dopaminergic deficits in a transgenic mouse model of Huntington's disease

Brain‐derived neurotrophic factor modulates dopaminergic deficits in a transgenic mouse model of Huntington's disease

Huntingtin protein interactions altered by polyglutamine expansion as determined by quantitative proteomic analysis

Bifunctional apoptosis inhibitor (BAR) protects neurons from diverse cell death pathways

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