Modifiers of mutant huntingtin aggregationfunctional conservation of C. elegans-modifiers of polyglutamine aggregation

Teuling, Eva; Bourgonje, Annika; Veenje, Sven; Thijssen, Karen L.; Boer, Jelle de; Velde, Joeri van der; Swertz, Morris A.; Nollen, Ellen A. A.

doi:10.1371/currents.rrn1255

Cited by 19 publications

(19 citation statements)

References 46 publications

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“…Both wild-type and mutant Htt co-purify with sev- eral translation-related proteins, co-fractionate with ribosomes, localize to stress granules, and inhibit translation when overexpressed in an in vitro assay. These observations are supported by genetic interaction screens where shRNA-mediated knockdown of proteins involved in protein synthesis enhanced aggregation of a polyglutamine-expanded N-terminal Htt fragment (53), which is in one way or another tied to disease outcome (70). This connection between HD and translation is further supported by the observation that the level of the kinase PKR, an inhibitor of cap-dependent translation, is elevated in HD patient brains (59).…”

Section: Discussionmentioning

confidence: 80%

“…4b, compare the upper and lower FLAG blots). Translation factors have a modifying effect on the aggregation and toxicity of N-terminal fragment-based models of mutant Htt toxicity in Caenorhabditis elegans and Saccharomyces cerevisiae (52,53). The differences in sedimentation profiles, mass spectrometry-identified protein associations, and the modifying effect that translation proteins have on mutant Htt toxicity in model systems suggest that mutant Htt may affect translation.…”

Section: ϫ10mentioning

confidence: 99%

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Proteomic Analysis of Wild-type and Mutant Huntingtin-associated Proteins in Mouse Brains Identifies Unique Interactions and Involvement in Protein Synthesis

Culver

Savas

Park

et al. 2012

Journal of Biological Chemistry

123

112

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Background: Differences in protein interactions between wild-type and mutant huntingtin are relevant to the disease. Results: Mutant huntingtin interacts with unique proteins and alters the subcellular context of some interactions shared with wild type. Conclusion: Mutant Huntington disease protein has loss-of-function and gain-of-function attributes. Significance: Results implicate understudied proteins and cellular/molecular processes that may contribute to the onset of the Huntington disease pathology.

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Section: Discussionmentioning

confidence: 80%

Section: ϫ10mentioning

confidence: 99%

Proteomic Analysis of Wild-type and Mutant Huntingtin-associated Proteins in Mouse Brains Identifies Unique Interactions and Involvement in Protein Synthesis

Culver

Savas

Park

et al. 2012

Journal of Biological Chemistry

123

112

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“…Tenascin‐R co‐aggregates with APP at nodes of Ranvier on myelinated axons (Xu et al ., 2014). Knockdown of UBA1 or talin‐2 increased aggregation of a polyglutamine array in C. elegans and of transgenic huntingtin (Htt‐Q74‐GFP) in cultured human HEK293 cells (Teuling et al ., 2011). Frame‐shifted misreading of ubiquitin‐B inhibits proteasomes in transgenic mice and phenotypically mimics AD (Irmler et al ., 2012).…”

Section: Discussionmentioning

confidence: 99%

Proteins that mediate protein aggregation and cytotoxicity distinguish Alzheimer's hippocampus from normal controls

et al. 2016

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SummaryNeurodegenerative diseases are distinguished by characteristic protein aggregates initiated by disease‐specific ‘seed’ proteins; however, roles of other co‐aggregated proteins remain largely unexplored. Compact hippocampal aggregates were purified from Alzheimer's and control‐subject pools using magnetic‐bead immunoaffinity pulldowns. Their components were fractionated by electrophoretic mobility and analyzed by high‐resolution proteomics. Although total detergent‐insoluble aggregates from Alzheimer's and controls had similar protein content, within the fractions isolated by tau or Aβ1–42 pulldown, the protein constituents of Alzheimer‐derived aggregates were more abundant, diverse, and post‐translationally modified than those from controls. Tau‐ and Aβ‐containing aggregates were distinguished by multiple components, and yet shared >90% of their protein constituents, implying similar accretion mechanisms. Alzheimer‐specific protein enrichment in tau‐containing aggregates was corroborated for individuals by three analyses. Five proteins inferred to co‐aggregate with tau were confirmed by precise in situ methods, including proximity ligation amplification that requires co‐localization within 40 nm. Nematode orthologs of 21 proteins, which showed Alzheimer‐specific enrichment in tau‐containing aggregates, were assessed for aggregation‐promoting roles in C. elegans by RNA‐interference ‘knockdown’. Fifteen knockdowns (71%) rescued paralysis of worms expressing muscle Aβ, and 12 (57%) rescued chemotaxis disrupted by neuronal Aβ expression. Proteins identified in compact human aggregates, bound by antibody to total tau, were thus shown to play causal roles in aggregation based on nematode models triggered by Aβ1–42. These observations imply shared mechanisms driving both types of aggregation, and/or aggregate‐mediated cross‐talk between tau and Aβ. Knowledge of protein components that promote protein accrual in diverse aggregate types implicates common mechanisms and identifies novel targets for drug intervention.

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“…We used TRiC reagents to rescue BDNF delivery. Suggesting that using TRiC may have an impact on HD pathogenesis, (i) wtHtt was found to interact with >700 cellular proteins, including CCT1 and CCT8 (57), and (ii) a Caenorhabditis elegans screening assay showed that six of eight CCT subunits suppressed mutant huntingtin aggregation (58). A technical challenge for using TRiC is that the TRiC complex consists of eight CCT subunits; introducing all eight subunits posed a daunting task.…”

Section: Impaired Lysosome Transport In Bachd Cortical Neurons Wasmentioning

confidence: 99%

TRiC subunits enhance BDNF axonal transport and rescue striatal atrophy in Huntington’s disease

Zhao

Chen

Han

et al. 2016

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

101

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Corticostriatal atrophy is a cardinal manifestation of Huntington's disease (HD). However, the mechanism(s) by which mutant huntingtin (mHTT) protein contributes to the degeneration of the corticostriatal circuit is not well understood. We recreated the corticostriatal circuit in microfluidic chambers, pairing cortical and striatal neurons from the BACHD model of HD and its WT control. There were reduced synaptic connectivity and atrophy of striatal neurons in cultures in which BACHD cortical and striatal neurons were paired. However, these changes were prevented if WT cortical neurons were paired with BACHD striatal neurons; synthesis and release of brain-derived neurotrophic factor (BDNF) from WT cortical axons were responsible. Consistent with these findings, there was a marked reduction in anterograde transport of BDNF in BACHD cortical neurons. Subunits of the cytosolic chaperonin T-complex 1 (TCP-1) ring complex (TRiC or CCT for chaperonin containing TCP-1) have been shown to reduce mHTT levels. Both CCT3 and the apical domain of CCT1 (ApiCCT1) decreased the level of mHTT in BACHD cortical neurons. In cortical axons, they normalized anterograde BDNF transport, restored retrograde BDNF transport, and normalized lysosomal transport. Importantly, treating BACHD cortical neurons with ApiCCT1 prevented BACHD striatal neuronal atrophy by enhancing release of BDNF that subsequently acts through tyrosine receptor kinase B (TrkB) receptor on striatal neurons. Our findings are evidence that TRiC reagentmediated reductions in mHTT enhanced BDNF delivery to restore the trophic status of BACHD striatal neurons., a genetically defined progressive neurodegenerative disorder, is characterized by abnormal involuntary movements, cognitive disability, and psychiatric symptoms (1). The pathogenesis of HD is due to an expanded CAG repeat in the huntingtin (HTT) gene, which encodes the protein Htt. Mutant Htt (mHTT) features an increased number of glutamines (Q > 36) near the N terminus. The striking atrophy and loss of striatal medium-sized spiny neurons (MSNs) in the HD brain are accompanied by atrophy of the cortex (2). The mechanisms by which mHTT induces dysfunction and death of neurons are actively explored (3). It has been shown that mHTT has an impact on axonal trafficking and signaling, synaptic function, gene expression, mitochondrial function, calcium homeostasis, and proteostasis (4, 5). Thus, mHTT plays a central role in HD pathogenesis, an assertion fully supported by recent studies in the BACHD model of HD (6).One productive line of inquiry regarding HD pathogenesis focuses on brain-derived neurotrophic factor (BDNF), which sustains neurons of the corticostriatal circuit (7-10). In the corticostriatal circuit, BDNF is produced in cortical neurons and is transported anterogradely in axons before secretion in striatum. Released BDNF binds to tyrosine receptor kinase B (TrkB) on striatal MSNs, resulting in BDNF-mediated signaling. Because MSNs do not produce BDNF, they are largely dependent on cortical neurons for i...

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Modifiers of mutant huntingtin aggregationfunctional conservation of C. elegans-modifiers of polyglutamine aggregation

Cited by 19 publications

References 46 publications

Proteomic Analysis of Wild-type and Mutant Huntingtin-associated Proteins in Mouse Brains Identifies Unique Interactions and Involvement in Protein Synthesis

Proteomic Analysis of Wild-type and Mutant Huntingtin-associated Proteins in Mouse Brains Identifies Unique Interactions and Involvement in Protein Synthesis

Proteins that mediate protein aggregation and cytotoxicity distinguish Alzheimer's hippocampus from normal controls

TRiC subunits enhance BDNF axonal transport and rescue striatal atrophy in Huntington’s disease

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