CHIP Suppresses Polyglutamine Aggregation and Toxicity<i>In Vitro</i>and<i>In Vivo</i>

Miller, Victor M.; Nelson, Rick F.; Gouvion, Cynthia M.; Williams, Ann E.; Rodríguez-Lebrón, Edgardo; Harper, Scott Q.; Davidson, Beverly L.; Rebagliati, Michael; Paulson, Henry L.

doi:10.1523/jneurosci.3001-05.2005

Cited by 224 publications

(221 citation statements)

References 49 publications

(78 reference statements)

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“…Several recent studies have implicated the unique U-box ubiquitin ligase CHIP as a necessary component for the sequestration and removal of aberrant proteins prone to aggregation in neurological disorders (Sahara et al, 2002;Urushitani et al, 2004;Miller et al, 2005). Despite these findings, a definitive link between ubiquitination of tau and its aggregation has yet to be established; however, several lines of correlative evidence do exist.…”

Section: Discussionmentioning

confidence: 99%

Deletion of the Ubiquitin Ligase CHIP Leads to the Accumulation, But Not the Aggregation, of Both Endogenous Phospho- and Caspase-3-Cleaved Tau Species

et al. 2006

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Accumulation of the microtubule-associated protein tau into neurofibrillary lesions is a pathological consequence of several neurodegenerative diseases, including Parkinson's disease and Alzheimer's disease. Hereditary mutations in the MAPT gene were shown to promote the formation of structurally distinct tau aggregates in patients that had a parkinsonian-like clinical presentation. Whether tau aggregates themselves or the soluble intermediate species that precede their aggregation are neurotoxic entities in these disorders has yet to be resolved; however, recent in vivo evidence supports the latter. We hypothesized that depletion of CHIP, a tau ubiquitin ligase, would lead to an increase in abnormal tau. Here, we show that deletion of CHIP in mice leads to the accumulation of non-aggregated, ubiquitinnegative, hyperphosphorylated tau species. CHIP Ϫ/Ϫ mice also have increased neuronal caspase-3 levels and activity, as well as caspasecleaved tau immunoreactivity. Overexpression of mutant (P301L) human tau in CHIP Ϫ/Ϫ mice is insufficient to promote either argyrophilic or "pre-tangle" structures, despite marked phospho-tau accumulation throughout the brain. These observations are supported in postdevelopmental studies using RNA interference for CHIP (chn-1) in Caenorhabditis elegans and cell culture systems. Our results demonstrate that CHIP is a primary component in the ubiquitin-dependent degradation of tau. We also show that hyperphosphorylation and caspase-3 cleavage of tau both occur before aggregate formation. Based on these findings, we propose that polyubiquitination of tau by CHIP may facilitate the formation of insoluble filamentous tau lesions.

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Section: Discussionmentioning

confidence: 99%

Deletion of the Ubiquitin Ligase CHIP Leads to the Accumulation, But Not the Aggregation, of Both Endogenous Phospho- and Caspase-3-Cleaved Tau Species

et al. 2006

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“…CHIP also interacts with misfolded proteins trapped by molecular chaperones and degrades them, thus acting as a "quality control" E3 (Cyr et al, 2002;Murata et al, 2003). In fact, CHIP suppressed inclusion formation and cellular toxicity in cell, zebrafish, and Drosophila polyQ disease models (Jana et al, 2005;Miller et al, 2005;Al-Ramahi et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

CHIP Overexpression Reduces Mutant Androgen Receptor Protein and Ameliorates Phenotypes of the Spinal and Bulbar Muscular Atrophy Transgenic Mouse Model

Adachi¹,

Waza²,

Tokui³

et al. 2007

J. Neurosci.

133

143

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Spinal and bulbar muscular atrophy (SBMA) is an inherited motor neuron disease caused by the expansion of a polyglutamine tract within the androgen receptor (AR). The pathologic features of SBMA are motor neuron loss in the spinal cord and brainstem and diffuse nuclear accumulation and nuclear inclusions of the mutant AR in the residual motor neurons and certain visceral organs. Many components of the ubiquitin-proteasome and molecular chaperones are also sequestered in the inclusions, suggesting that they may be actively engaged in an attempt to degrade or refold the mutant AR. C terminus of Hsc70 (heat shock cognate protein 70)-interacting protein (CHIP), a U-box type E3 ubiquitin ligase, has been shown to interact with heat shock protein 90 (Hsp90) or Hsp70 and ubiquitylates unfolded proteins trapped by molecular chaperones and degrades them. Here, we demonstrate that transient overexpression of CHIP in a neuronal cell model reduces the monomeric mutant AR more effectively than it does the wild type, suggesting that the mutant AR is more sensitive to CHIP than is the wild type. High expression of CHIP in an SBMA transgenic mouse model also ameliorated motor symptoms and inhibited neuronal nuclear accumulation of the mutant AR. When CHIP was overexpressed in transgenic SBMA mice, mutant AR was also preferentially degraded over wild-type AR. These findings suggest that CHIP overexpression ameliorates SBMA phenotypes in mice by reducing nuclear-localized mutant AR via enhanced mutant AR degradation. Thus, CHIP overexpression would provide a potential therapeutic avenue for SBMA.

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“…Consequently, the hallmarks of polyQ disorders are nuclear inclusions (NIs) containing aggregated mutant proteins in affected neurons (Di Figlia et al, 1997;Paulson et al, 1997;Skinner et al, 1997). Although toxicity of NIs per se can be debated, a number of studies suggest deregulation of cellular components involved in folding and/or degradation of proteins as a possible mechanism of disease pathogenesis (Warrick et al, 1999;Bence et al, 2001;Miller et al, 2005;Vacher et al, 2005;Waza et al, 2005). Protein misfolding is expected to induce cellular stress response, including the activation of the JNK/cJun/AP-1 signaling pathway (Sherman and Goldberg, 2001;Nishitoh et al, 2002;Merienne et al, 2003;Garcia et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Preventing polyglutamine-induced activation of c-Jun delays neuronal dysfunction in a mouse model of SCA7 retinopathy

Mérienne¹,

Friedman²,

Akimoto³

et al. 2007

Neurobiology of Disease

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We have approached the role of cellular stress in neurodegenerative diseases caused by polyglutamine expansion (polyQ) in the context of Spinocerebellar ataxia type 7 (SCA7) that includes retinal degeneration. Using the R7E mouse, in which polyQ-ataxin-7 is specifically over-expressed in rod photoreceptors, we previously showed that rod dysfunction correlated to moderate and prolonged activation of the JNK/c-Jun stress pathway. SCA7 retinopathy was also associated with reduced expression of rod-specific genes, including the transcription factor Nrl, which is essential for rod differentiation and function. Here, we report that R7E retinopathy is improved upon breeding with the JunAA knock-in mice, in which JNK-mediated activation of c-Jun is compromised. Expression of Nrl and its downstream targets, which are involved in phototranduction, are partially restored in the JunAA-R7E mice. We further show that c-Jun can directly repress the transcription of Nrl. Our studies suggest that polyQ-induced cellular stress leads to repression of genes necessary for neuronal fate and function.

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CHIP Suppresses Polyglutamine Aggregation and ToxicityIn VitroandIn Vivo

Cited by 224 publications

References 49 publications

Deletion of the Ubiquitin Ligase CHIP Leads to the Accumulation, But Not the Aggregation, of Both Endogenous Phospho- and Caspase-3-Cleaved Tau Species

Deletion of the Ubiquitin Ligase CHIP Leads to the Accumulation, But Not the Aggregation, of Both Endogenous Phospho- and Caspase-3-Cleaved Tau Species

CHIP Overexpression Reduces Mutant Androgen Receptor Protein and Ameliorates Phenotypes of the Spinal and Bulbar Muscular Atrophy Transgenic Mouse Model

Preventing polyglutamine-induced activation of c-Jun delays neuronal dysfunction in a mouse model of SCA7 retinopathy

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