Normal huntingtin function: an alternative approach to Huntington's disease

Cattaneo, Elena; Zuccato, Chiara; Tartari, Marzia

doi:10.1038/nrn1806

Cited by 579 publications

(328 citation statements)

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“…Htt is also believed to play a role in vesicle transport and in regulating gene transcription and RNA trafficking (Cattaneo et al, 2005;Finkbeiner, 2011;Ross and Tabrizi, 2011;Zuccato et al, 2010). Therefore, HD involves both loss-of-function of the normal Htt that impairs its fundamental role in neuronal cells, and predominantly gain-of-function by the mutant Htt proteins that form amyloid-like inclusions ).…”

Section: Ii431 Huntington's Diseasementioning

confidence: 99%

Firefly luciferase mutants as sensors of proteome stress

et al. 2011

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Section: Ii431 Huntington's Diseasementioning

confidence: 99%

Firefly luciferase mutants as sensors of proteome stress

et al. 2011

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“…HD is a neurodegenerative disorder caused by a multiple CAG expansion in exon1 of huntingtin (htt) gene (Kremer et al, 1994), producing a significant dysfunction and neural death, especially in the medium spiny neurons of the striatum. Htt is a ubiquitously expressed large protein that participates in a plethora of functions, including clathrin-mediated endocytosis, vesicle transport, transcriptional regulation, and cell survival (for review, see Harjes and Wanker, 2003;Cattaneo et al, 2005). In relation to BDNF, htt enhances the transcription of BDNF by the inhibition of the neuron restrictive silencer element (Zuccato et al, 2003) and promotes the transport of BDNF-containing vesicles along microtubules (Gauthier et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Mutant huntingtin Impairs the Post-Golgi Trafficking of Brain-Derived Neurotrophic Factor But Not Its Val66Met Polymorphism

Toro¹,

Canals²,

Ginés³

et al. 2006

J. Neurosci.

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“…Many proteins have been demonstrated to interact with WT Htt and/or mutant Htt, and their functions support some of the mechanisms perturbed in HD, which include transcription, signaling, trafficking/endocytosis, and metabolism/mitochondrial functions (5)(6)(7)(8)(9)(10). However, Htt's precise function has proven elusive, and our poor understanding of its function remains a limiting factor to the development of successful therapeutics (11). Proteolytic processing of WT and mutant Htt has been investigated extensively and appears to play a critical role in disease pathogenesis.…”

mentioning

confidence: 99%

Huntington's disease protein contributes to RNA-mediated gene silencing through association with Argonaute and P bodies

Savas

Makusky

Ottosen

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

154

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Huntington's disease is a dominant autosomal neurodegenerative disorder caused by an expansion of polyglutamines in the huntingtin (Htt) protein, whose cellular function remains controversial. To gain insight into Htt function, we purified epitope-tagged Htt and identified Argonaute as associated proteins. Colocalization studies demonstrated Htt and Ago2 to be present in P bodies, and depletion of Htt showed compromised RNA-mediated gene silencing. Mouse striatal cells expressing mutant Htt showed fewer P bodies and reduced reporter gene silencing activity compared with wild-type counterparts. These data suggest that the previously reported transcriptional deregulation in HD may be attributed in part to mutant Htt's role in post-transcriptional processes.microRNA ͉ poly-glutamine ͉ RNA interference ͉ post-transcriptional gene silencing ͉ neuronal RNA granule H untington's disease (HD) is caused by an expansion of the polymorphic stretch of uninterrupted CAG trinucleotide repeats in exon 1 of the IT15 gene, resulting in a long tract of polyglutamine (polyQ) in the N terminus of the HD protein huntingtin (Htt) (1). The human Htt protein contains 3,144 amino acids, and the polyQ stretch starts at the 18th amino acid, followed by a polyproline (polyP) sequence; the remaining portion of the protein is likely to be rich in ␣-helices, many of which compose HEAT repeats (2). The length of the glutamine repeats in the unaffected population varies from 6 to 35; HD is caused by expansion to 36 or more repeats (3, 4). HD is a member of a group of at least nine diseases caused by CAG repeat expansions that includes spinocerebellar ataxias (SCAs) 1-3, 6, 7, and 17, spinobulbar muscular atrophy, and dentatorubral-pallidoluysian atrophy. The protein that is subject to polyQ expansion in each disease appears to be unrelated, and despite their widespread expression in the brain and other tissues, mutation in each protein leads to distinct characteristic neurodegeneration patterns.Htt is expressed in a variety of tissues both within and outside of the nervous system. Many proteins have been demonstrated to interact with WT Htt and/or mutant Htt, and their functions support some of the mechanisms perturbed in HD, which include transcription, signaling, trafficking/endocytosis, and metabolism/mitochondrial functions (5-10). However, Htt's precise function has proven elusive, and our poor understanding of its function remains a limiting factor to the development of successful therapeutics (11). Proteolytic processing of WT and mutant Htt has been investigated extensively and appears to play a critical role in disease pathogenesis. Caspase-6 cleavage at amino acid 586 in mouse Htt and the release of the N-terminal Htt fragment are required for neuronal dysfunction and degeneration in an HD mouse model (12), but the basis for the need for this cleavage is unclear.We set out to search for binding proteins to elucidate the normal function of Htt. We chose a biochemical approach to purify proteins associated with WT and mutant Htt and ide...

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Normal huntingtin function: an alternative approach to Huntington's disease

Cited by 579 publications

References 147 publications

Firefly luciferase mutants as sensors of proteome stress

Firefly luciferase mutants as sensors of proteome stress

Mutant huntingtin Impairs the Post-Golgi Trafficking of Brain-Derived Neurotrophic Factor But Not Its Val66Met Polymorphism

Huntington's disease protein contributes to RNA-mediated gene silencing through association with Argonaute and P bodies

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