Glutamine/proline-rich PQE-1 proteins protect
            <i>Caenorhabditis elegans</i>
            neurons from huntingtin polyglutamine neurotoxicity

Faber, Peter W.; Voisine, Cindy; King, Daphne C.; Bates, Emily A.; Hart, Anne C.

doi:10.1073/pnas.262544899

Cited by 111 publications

(84 citation statements)

References 57 publications

(59 reference statements)

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“…The Sup35 PrD, NM, not only suppresses polyQ-expanded Htt exon-1 toxicity in yeast and human cells as shown in this report but also suppresses polyQ-expanded SCA3 toxicity in Drosophila (43). As noted above, interaction between Q-rich proteins and polyQ-expanded disease proteins frequently leads to enhanced toxicity, but clearly, there are examples of beneficial interactions like those reported here in yeast and previously in C. elegans (44). No doubt the phenotypic outcome will depend on the expression patterns of the Q-rich proteins, as well as their posttranslational modifications, in the context of a particular proteome.…”

Section: Discussionsupporting

confidence: 60%

Prion-like proteins sequester and suppress the toxicity of huntingtin exon 1

Kayatekin

Matlack

Hesse

et al. 2014

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

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Expansions of preexisting polyglutamine (polyQ) tracts in at least nine different proteins cause devastating neurodegenerative diseases. There are many unique features to these pathologies, but there must also be unifying mechanisms underlying polyQ toxicity. Using a polyQ-expanded fragment of huntingtin exon-1 (Htt103Q), the causal protein in Huntington disease, we and others have created tractable models for investigating polyQ toxicity in yeast cells. These models recapitulate key pathological features of human diseases and provide access to an unrivalled genetic toolbox. To identify toxicity modifiers, we performed an unbiased overexpression screen of virtually every protein encoded by the yeast genome. Surprisingly, there was no overlap between our modifiers and those from a conceptually identical screen reported recently, a discrepancy we attribute to an artifact of their overexpression plasmid. The suppressors of Htt103Q toxicity recovered in our screen were strongly enriched for glutamine-and asparagine-rich prion-like proteins. Separated from the rest of the protein, the prion-like sequences of these proteins were themselves potent suppressors of polyQ-expanded huntingtin exon-1 toxicity, in both yeast and human cells. Replacing the glutamines in these sequences with asparagines abolished suppression and converted them to enhancers of toxicity. Replacing asparagines with glutamines created stronger suppressors. The suppressors (but not the enhancers) coaggregated with Htt103Q, forming large foci at the insoluble protein deposit in which proteins were highly immobile. Cells possessing foci had fewer (if any) small diffusible oligomers of Htt103Q. Until such foci were lost, cells were protected from death. We discuss the therapeutic implications of these findings.protein misfolding | prions P rotein misfolding and aggregation underlie many neurodegenerative diseases. The causes of protein misfolding are numerous and include single amino acid changes and expansions of amino acid repeats. Polyglutamine (polyQ) expansions are an infamous example of the latter and are responsible for at least nine neurodegenerative conditions, including Huntington disease (HD). In most of these diseases the polyQ-expanded protein is expressed throughout the body, but tissue damage is restricted to the nervous system and, often, to a subset of cells depending on the causal protein. Thus, there are important cell type-specific determinants of toxicity, and these are specific to particular proteins. Despite these differences, disease severity is tightly linked to the number of glutamines. Progressively earlier onset occurs as the number of glutamines increases beyond a critical threshold of ∼35-45 residues (1). Moreover, in all cases, pathology is associated with misfolded forms of the polyQ-expanded protein.Thus, common features that arise from the expansions and result from shared aspects of polyQ-driven protein misfolding must contribute to pathology. Given the diverse nature of both the proteins bearing the polyQ tract and t...

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Section: Discussionsupporting

confidence: 60%

Prion-like proteins sequester and suppress the toxicity of huntingtin exon 1

Kayatekin

Matlack

Hesse

et al. 2014

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

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“…Several transgenic C. elegans lines have been successfully established to study human neurodegenerative disorders (35)(36)(37)(38)(39)(40). Such heterologous genetic models have proven to be very useful for understanding disease pathogenesis and developing therapeutic strategy.…”

Section: Discussionmentioning

confidence: 99%

Disrupted-in-Schizophrenia 1–mediated axon guidance involves TRIO-RAC-PAK small GTPase pathway signaling

Chen

Huang

Cheng

2011

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

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Defects in neuronal connectivity of the brain are well documented among schizophrenia patients. Although the schizophrenia susceptibility gene Disrupted-in-Schizophrenia 1 (DISC1) has been implicated in various neurodevelopmental processes, its role in regulating axonal connections remains elusive. Here, a heterologous DISC1 transgenic system in the relatively simple and wellcharacterized Caenorhabditis elegans motor neurons has been established to investigate whether DISC1 regulates axon guidance during development. Transgenic DISC1 in C. elegans motor neurons is enriched in the migrating growth cones and causes guidance defects of their growing axons. The abnormal axonal phenotypes induced by DISC1 are similar to those by gain-of-function rac genes. In vivo genetic interaction studies revealed that the UNC-73/TRIO-RAC-PAK signaling pathway is activated by ectopic DISC1 in C. elegans motor axons. Using in vitro GST pull-down and coimmunoprecipitation assays, we found that DISC1 binds specifically to the amino half of spectrin repeats of TRIO, thereby preventing TRIO's amino half of spectrin repeats from interacting with its first guanine nucleotide exchange factor (GEF) domain, GEF1, and facilitating the recruitment of RAC1 to TRIO. In cultured mammalian cells, RAC1 is activated by increased TRIO's GEF activity when DISC1 is present. These results together indicate that the TRIO-RAC-PAK signaling pathway can be exploited and modulated by DISC1 to regulate axonal connectivity in the developing brain.genetic model | rolipram S chizophrenia is a neurodevelopmental disorder with genetic predispositions (1, 2). Although the etiology and neuropathology of schizophrenia are still elusive, functional and neuroanatomical studies from patients have documented various abnormalities in the diseased brain. In particular, defects in neuronal connectivity during development have been proposed as an important precipitating factor for schizophrenia, which is thought to be unmasked by other developmental events or environmental stressors later in life (3). It is therefore likely that some of the major schizophrenia susceptibility genes are important for regulating axonal connections during development.In recent years, the effort to search for genes susceptible to schizophrenia has led to the identification of the Disrupted-inSchizophrenia 1 (DISC1) gene, whose mutation is highly associated with schizophrenia and other major human mental diseases (4). DISC1 has roles in neuron proliferation, neuron migration, axon outgrowth, and synapse formation/maturation (5-8). In our previous studies, we identified an unexpected role of DISC1 in regulating the guidance of developing axons in the adult-born hippocampal dentate granule cells (5, 9). These effects expand the known functions of DISC1 but sheds little light on how DISC1 effects axon guidance.To systemically study the role of DISC1 in axon guidance and to identify the signaling pathways that might be involved, we set out to establish a heterologous genetic system in the nematode Ca...

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“…115 These C. elegans models have been used to investigate proteins involved in aging and aggregation, as well as drug testing. [117][118][119][120] However, neuronal cell death is not robust in these HD C. elegans models.…”

Section: Animal Models Of Huntington's Diseasementioning

confidence: 99%