Huntingtin is required for neurogenesis and is not impaired by the Huntington's disease CAG expansion

White, Jacqueline K.; Auerbach, Wojtek; Duyao, Mabel P.; Vonsattel, Jean‐Paul; Gusella, James F.; Joyner, Alexandra L.; MacDonald, Marcy E.

doi:10.1038/ng1297-404

Cited by 471 publications

(348 citation statements)

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“…Previous work demonstrated that homozygous mice with a targeted disruption in the Htt gene do not survive to term and suffer early postimplantation embryonic lethality (Duyao et al, 1995;Nasir et al, 1995;Zeitlin et al, 1995;White et al, 1997). More recent morphometric and ultrastructural analysis performed on heterozygous mice, which survive to adulthood, identified neuronal loss with signs of apoptosis in the basal ganglia of adult animals (O'Kusky et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

“…Mice with a targeted disruption of the Htt gene die at embryonic day 7.5 (Duyao et al, 1995;Nasir et al, 1995;Zeitlin et al, 1995). Moreover, analysis of mice expressing Ͻ50% of wtHtt showed extensive brain abnormalities and died shortly after birth (White et al, 1997). These data suggest that Htt is an important factor during embryonic development and that its role is not restricted to the nervous system.…”

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confidence: 89%

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Wild-Type Huntingtin Protects from Apoptosis Upstream of Caspase-3

et al. 2000

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Expansion of a polyglutamine sequence in the N terminus of huntingtin is the gain-of-function event that causes Huntington's disease. This mutation affects primarily the medium-size spiny neurons of the striatum. Huntingtin is expressed in many neuronal and non-neuronal cell types, implying a more general function for the wild-type protein. Here we report that wild-type huntingtin acts by protecting CNS cells from a variety of apoptotic stimuli, including serum withdrawal, death receptors, and pro-apoptotic Bcl-2 homologs. This protection may take place at the level of caspase-9 activation. The full-length protein also modulates the toxicity of the poly-Q expansion. Cells expressing full-length mutant protein are susceptible to fewer death stimuli than cells expressing truncated mutant huntingtin.

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Section: Discussionmentioning

confidence: 99%

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confidence: 89%

Wild-Type Huntingtin Protects from Apoptosis Upstream of Caspase-3

et al. 2000

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“…Two interesting peculiarities arose from previous investigations, that could explain the pathogenic phenomenon of expanded polyglutamines: their increasing ability to form amyloid-like protein aggregates with the elongation of the polyQ stretches [10,14,15], and the specific capability to be recognized by the 1C2 and 1F8 MoAbs [20,21], Abs whose affinity increases with the elongation of the polyQ stretches.…”

Section: Introductionmentioning

confidence: 99%

Phenotypic effects of expanded ataxin-1 polyglutamines with interruptions in vitro

Calabresi

Guida

Servadio³

et al. 2001

Brain Research Bulletin

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Spinocerebellar ataxia type 1 is a neurodegenerative disease caused by expansion of an uninterrupted glutamine repeat in ataxin-1 protein. Protein aggregation and immunoreactivity to 1C2 monoclonal antibody are two distinct pathognomonic features of expanded ataxin-1, as well as of other polyglutamine disorders. Rare cases of non-affected elderly subjects carrying expanded ataxin-1 alleles were found in random population. However, in these alleles the glutamine stretch was interrupted by histidines. Due to lack of phenotype, these alleles should be considered "normal". Most importantly, occurrence of these unusual alleles provides a unique opportunity to investigate which molecular properties of expanded ataxin-1 are not coupled to polyglutamine pathogenesis. Towards this goal, we compared in vitro the immunoreactivity to 1C2 antibody and the ability to form aggregates of interrupted and uninterrupted alleles. Immunoblotting showed that expandedinterrupted ataxin-1 had an affinity to 1C2 resembling that of normal ataxin-1. On the contrary, filter assay showed that aggregation rate of expanded-interrupted ataxin-1 resembles that of expanded-uninterrupted ataxin-1. These observations indicate that affinity for 1C2 does not directly correlate with selfaggregation of ataxin-1. Moreover, self-aggregation is not directly affected by histidine interruptions. In conclusion, these results support the hypothesis that mechanisms underlying neuronal degeneration are triggered by protein misfolding rather than by protein aggregation. © 2001 Elsevier Science Inc.KEY WORDS: Spinocerebellar ataxia type 1, SCA1, Trinucleotide expansion, Amyloid-like protein aggregates.

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“…Hdh knock-in Mice. White et al (1997) developed a mouse model of Huntington's disease by extending the polyglutamine tract of the murine homolog (Hdh) of the human huntingtin gene (HD). CAG repeats from an HD chromosome were inserted into the appropriate position in Hdh exon 1, altering the mouse HD homolog to encode huntingtin protein with 50, 92, or 111 glutamine residues, instead of the 7 normally found in the mouse protein.…”

Section: Transgenic Mice Expressing Full-length Human Mutant Huntingtinmentioning

confidence: 99%

Bioenergetic Defects and Oxidative Damage in Transgenic Mouse Models of Neurodegenerative Disorders

Browne¹

2003

PsycEXTRA Dataset

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Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to Washington Headquarters Services, Directorate for Information Operations and Reports, 1215 Jefferson Davis Highway, Suite 1204, Arlington, VA 22202-4302, and PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES)Weill Medical College of Cornell university New York, New York 10021 E-Mail: sub2001@med.cornell.edu This project aims to determine the roles of bioenergetic dysfunction and oxidative stress in mechanisms of neurodegeneration in Huntingtons disease (HD) and familial amyotrophic lateral sclerosis. Studies in this second year extended the first year's investigations into cerebral glucose metabolism in mutant mouse models of HD. We found increases in cerebral glucose use in forebrain regions of 4 month-old Hdh "knock-in" mice expressing a mutant 92 glutamine stretch in huntingtin protein (Hdh Q92 ), relative to levels in wild-type mice (Hdh Q7 ). Metabolic changes precede pathologic changes and show a gene-dosage effect, homozygote Hdh Q92 mice showing larger magnitude changes than heterozygotes. We attempted to measure similar parameters in R6/2 HD mice, but experiments were hindered by the diabetic profile of these mice. However, findings in another HD mouse model (N171-82Q) also show pre-symptomatic cerebral glucose use elevations associated with the gene mutation. Results from years 1 and 2 suggest that mutant huntingtin expression induces metabolic abnormalities that precede symptom onset and pathological events in these mouse HD models. Further, the occurrence of metabolic changes is dependent on poly glutamine repeat length and gene dosage. These findings represent significant progress towards the original goals of this proposal. Where copyrighted material is quoted, permission has been obtained to use such material. SPONSORING / MONITORING AGENCY NAME(S) AND ADDRESS(ES)U SUBJECT TERMSWhere material from documents designated for limited distribution is quoted, permission has been obtained to use the material.Citations of commercial organizations and trade names in this report do not constitute an official Department of Army endorsement or approval of the products or services of these organizations.*>* * S In conducting research using animals, the investigator(s) adhered to the "Guide for the Care and Use of Laboratory Animals," prepared by the Committee on Care and use of Laboratory Animals of the Institute of Laboratory Resources, national Research Council (NIH Publication No. 86-23, Revised 1985).For the protection of human subjects, the investigator(s) adhered to policies of applicable Federal Law 45 CFR 46.In conducting research utilizing recombinant DNA technology, the...

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Huntingtin is required for neurogenesis and is not impaired by the Huntington's disease CAG expansion

Cited by 471 publications

References 42 publications

Wild-Type Huntingtin Protects from Apoptosis Upstream of Caspase-3

Wild-Type Huntingtin Protects from Apoptosis Upstream of Caspase-3

Phenotypic effects of expanded ataxin-1 polyglutamines with interruptions in vitro

Bioenergetic Defects and Oxidative Damage in Transgenic Mouse Models of Neurodegenerative Disorders

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