Abstract：
:Huntington's disease (HD) is an autosomal-dominant neurodegenerative disorder caused by a poly-glutamine expansion in huntingtin, the protein encoded by the HD gene. PolyQ-expanded huntingtin is toxic to neurons, especially the medium spiny neurons of the striatum. At the same time, wild-type huntingtin has important - indeed essential - protective functions. Any effective molecular therapy must preserve the expression of wild-type huntingtin, while silencing the mutant allele. We hypothesized that an appropriate siRNA molecule would display the requisite specificity and efficacy. As RNA interference is incapable of distinguishing among alleles with varying numbers of CAG (glutamine) codons, another strategy is needed. We used HD fibroblasts in which the pathogenic mutation is linked to a polymorphic site: the Delta2642 deletion of one of four tandem GAG triplets. We silenced expression of the harmful Delta2642-marked polyQ-expanded huntingtin without compromising synthesis of its wild-type counterpart. Following this success in HD fibroblasts, we obtained similar results with neuroblastoma cells expressing both wild-type and mutant HD genes. As opposed to the effect of depleting wild-type huntingtin, specifically silencing the mutant species actually lowered caspase-3 activation and protected HD cells under stress conditions. These findings have therapeutic implications not only for HD, but also for other autosomal dominant diseases. This approach has great promise: it may lead to personalized genetic therapy, a holy grail in contemporary medicine.
journal_name
J Neurochemjournal_title
Journal of neurochemistryauthors
Zhang Y,Engelman J,Friedlander RMdoi
10.1111/j.1471-4159.2008.05734.xsubject
Has Abstractpub_date
2009-01-01 00:00:00pages
82-90issue
1eissn
0022-3042issn
1471-4159pii
JNC5734journal_volume
108pub_type
杂志文章abstract：:An acid-hydrolyzable conjugate of 3,4-dihydroxyphenylethylamine (dopamine, DA) was detected in superfusates from slices from rat striatum. The concentrations of endogenous free and conjugated DA, and of the acid metabolites (3,4-dihydroxyphenylacetic acid [DOPAC] and homovanillic acid [HVA]) in superfusates were measu...
journal_title：Journal of neurochemistry
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doi：10.1046/j.1471-4159.1994.62010113.x
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journal_title：Journal of neurochemistry
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journal_title：Journal of neurochemistry
pub_type： 杂志文章
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更新日期：1996-01-01 00:00:00
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doi：10.1111/j.1471-4159.2008.05590.x
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journal_title：Journal of neurochemistry
pub_type： 杂志文章
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doi：10.1046/j.1471-4159.1997.69062477.x
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journal_title：Journal of neurochemistry
pub_type： 杂志文章
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更新日期：2006-04-01 00:00:00
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更新日期：2007-07-01 00:00:00
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journal_title：Journal of neurochemistry
pub_type： 杂志文章
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journal_title：Journal of neurochemistry
pub_type： 杂志文章
doi：10.1111/j.1471-4159.1990.tb08822.x
更新日期：1990-07-01 00:00:00
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journal_title：Journal of neurochemistry
pub_type： 杂志文章
doi：10.1111/j.1471-4159.1992.tb09323.x
更新日期：1992-01-01 00:00:00
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journal_title：Journal of neurochemistry
pub_type： 杂志文章
doi：10.1111/j.1471-4159.1989.tb10929.x
更新日期：1989-01-01 00:00:00
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journal_title：Journal of neurochemistry
pub_type： 杂志文章
doi：10.1111/j.1471-4159.1986.tb02852.x
更新日期：1986-07-01 00:00:00
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journal_title：Journal of neurochemistry
pub_type： 杂志文章
doi：10.1046/j.1471-4159.1995.64041622.x
更新日期：1995-04-01 00:00:00
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journal_title：Journal of neurochemistry
pub_type： 杂志文章
doi：10.1111/j.1471-4159.1986.tb12945.x
更新日期：1986-01-01 00:00:00
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journal_title：Journal of neurochemistry
pub_type： 杂志文章
doi：10.1046/j.1471-4159.2001.00412.x
更新日期：2001-07-01 00:00:00
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pub_type： 杂志文章
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更新日期：2020-08-16 00:00:00
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journal_title：Journal of neurochemistry
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doi：10.1111/j.1471-4159.1992.tb11332.x
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journal_title：Journal of neurochemistry
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更新日期：2004-06-01 00:00:00
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journal_title：Journal of neurochemistry
pub_type： 杂志文章
doi：10.1046/j.1471-4159.2001.00281.x
更新日期：2001-05-01 00:00:00
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doi：
更新日期：1999-11-01 00:00:00
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journal_title：Journal of neurochemistry
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doi：10.1046/j.1471-4159.2003.01861.x
更新日期：2003-08-01 00:00:00
abstract：:The uptake of amino acids by microvessels isolated from brains of rats was studied. Previous studies have demonstrated alterations in blood-brain amino acid transport after portacaval shunt in rats. In order to elucidate whether such changes in the blood-brain barrier were located in the microvessels, brain microvesse...
journal_title：Journal of neurochemistry
pub_type： 杂志文章
doi：10.1111/j.1471-4159.1981.tb01635.x
更新日期：1981-02-01 00:00:00
abstract：:Exposure of neurones in culture to excitotoxic levels of glutamate results in an initial transient spike in [Ca2+]i followed by a delayed, irreversible [Ca2+]i rise governed by rapid kinetics, with Ca2+ originating from the extracellular medium. The molecular mechanism responsible for the secondary Ca2+ rise is unknow...
journal_title：Journal of neurochemistry
pub_type： 杂志文章
doi：10.1111/j.1471-4159.2004.02732.x
更新日期：2004-10-01 00:00:00
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journal_title：Journal of neurochemistry
pub_type： 杂志文章
doi：10.1046/j.1471-4159.1997.69010365.x
更新日期：1997-07-01 00:00:00
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journal_title：Journal of neurochemistry
pub_type： 杂志文章,评审
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更新日期：2019-07-01 00:00:00
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journal_title：Journal of neurochemistry
pub_type： 杂志文章
doi：10.1111/j.1471-4159.2012.07860.x
更新日期：2012-09-01 00:00:00
abstract：:To examine the effects of glutamatergic neurotransmission on amyloid processing, we stably expressed the metabotropic glutamate receptor subtype 1alpha (mGlu-R1alpha) in HEK 293 cells. Both glutamate and the selective metabotropic agonist 1-amino-1,3-cyclopentanedicarboxylic acid (ACPD) rapidly increased phosphatidyli...
journal_title：Journal of neurochemistry
pub_type： 杂志文章
doi：10.1046/j.1471-4159.1997.69020704.x
更新日期：1997-08-01 00:00:00
abstract：:Synaptic scaffolding molecule (S-SCAM) is a synaptic protein, which harbors five or six PSD-95/Discs large/ZO-1 (PDZ), a guanylate kinase and two WW domains. It interacts with NMDA receptor subunits, neuroligin and beta-catenin, and is involved in the accumulation of neuroligin at excitatory synapses. In this study, w...
journal_title：Journal of neurochemistry
pub_type： 杂志文章
doi：10.1111/j.1471-4159.2006.04170.x
更新日期：2007-01-01 00:00:00
