Modeling Polyglutamine Pathogenesis in C. elegans

Brignull, Heather R.; Morley, James F.; Garcia, Susana M. D. A.; Morimoto, Richard I.

doi:10.1016/s0076-6879(06)12016-9

Cited by 84 publications

(74 citation statements)

References 72 publications

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“…The N-rich variant of Q103, N47, as well as highly aggregation-prone variants of NM (NM*, NM N , and NM Q ) all showed a diffuse cytosolic localization but exhibited a small amount of aggregated material, which may result from a small population of stressed or aged cells. This is in stark contrast to observations made in S. cerevisiae, C. elegans, D. melanogaster, and mammalian cells, where all tested proteins aggregate in the cytosol (31,(47)(48)(49)64). Moreover, the expression of prion-like proteins in these organisms was detrimental, because of cytotoxic effects (31,(47)(48)(49)64).…”

Section: Discussioncontrasting

confidence: 93%

“…This is in stark contrast to observations made in S. cerevisiae, C. elegans, D. melanogaster, and mammalian cells, where all tested proteins aggregate in the cytosol (31,(47)(48)(49)64). Moreover, the expression of prion-like proteins in these organisms was detrimental, because of cytotoxic effects (31,(47)(48)(49)64). However, in D. discoideum, the expression of prion-like proteins did not lead to measurable effects on cellular health during the vegetative cycle or development.…”

Section: Discussioncontrasting

confidence: 93%

“…Studies with several different model organisms have shown that the expression of polyQ-containing proteins is associated with protein aggregation in the cytosol and cytotoxic effects (31,47,48). Surprisingly, however, we did not observe cytosolic aggregates for any of the tested prion-like proteins.…”

Section: Discussioncontrasting

confidence: 86%

“…To identify mechanisms controlling the aggregation of prion-like proteins in D. discoideum, we first studied the aggregation behavior of several well-characterized prion-like proteins. These proteins have been studied extensively in other organisms and have been shown to form cytosolic aggregates in S. cerevisiae, C. elegans, and mammalian cells (28,(30)(31)(32). In this study, we used the polyQ-containing exon 1 of human huntingtin with 103 consecutive glutamines (Q103) and a synthetic polyasparagine variant in which the glutamines were replaced by asparagines (N47), to account for the extreme N-richness of D. discoideum.…”

Section: Aggregation-prone Prion-like Proteins Do Not Aggregate In Thementioning

confidence: 99%

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Dictyostelium discoideum has a highly Q/N-rich proteome and shows an unusual resilience to protein aggregation

Malinovska

Palm

Gibson

et al. 2015

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

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Many protein-misfolding diseases are caused by proteins carrying prion-like domains. These proteins show sequence similarity to yeast prion proteins, which can interconvert between an intrinsically disordered and an aggregated prion state. The natural presence of prions in yeast has provided important insight into disease mechanisms and cellular proteostasis. However, little is known about prions in other organisms, and it is not yet clear whether the findings in yeast can be generalized. Using bioinformatics tools, we show that Dictyostelium discoideum has the highest content of prion-like proteins of all organisms investigated to date, suggesting that its proteome has a high overall aggregation propensity. To study mechanisms regulating these proteins, we analyze the behavior of several well-characterized prion-like proteins, such as an expanded version of human huntingtin exon 1 (Q103) and the prion domain of the yeast prion protein Sup35 (NM), in D. discoideum. We find that these proteins remain soluble and are innocuous to D. discoideum, in contrast to other organisms, where they form cytotoxic cytosolic aggregates. However, when exposed to conditions that compromise molecular chaperones, these proteins aggregate and become cytotoxic. We show that the disaggregase Hsp101, a molecular chaperone of the Hsp100 family, dissolves heat-induced aggregates and promotes thermotolerance. Furthermore, prion-like proteins accumulate in the nucleus, where they are targeted by the ubiquitin-proteasome system. Our data suggest that D. discoideum has undergone specific adaptations that increase the proteostatic capacity of this organism and allow for an efficient regulation of its prion-like proteome. molecular chaperones | proteostasis | Dictyostelium discoideum | protein aggregation | prion

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Section: Discussioncontrasting

confidence: 93%

Section: Discussioncontrasting

confidence: 93%

Section: Discussioncontrasting

confidence: 86%

Section: Aggregation-prone Prion-like Proteins Do Not Aggregate In Thementioning

confidence: 99%

See 2 more Smart Citations

Dictyostelium discoideum has a highly Q/N-rich proteome and shows an unusual resilience to protein aggregation

Malinovska

Palm

Gibson

et al. 2015

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

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“…Mice transgenic for exon 1 of huntingtin containing highly expanded glutamine-codons, recapitulate some features of human pathology and develop severe neurological deficits resembling Huntington's disease, such as chorea, tremor, and epileptic seizures (13). Expression of mutant huntingtin in mammalian cells, Drosophila, yeast, and Caenorhabditis all result in inclusion formation and toxicity relative to nonmutant forms of huntingtin, which supports the hypothesis that processes associated with the aggregation of these polyQ-containing proteins causes an inherent gain of toxic function (14)(15)(16). Like the glutamine expansions, alanine expansions also seem to promote inclusion formation of their host protein (8,17) suggesting that such effects may be more widespread for other polyamino acid repeats found in other proteins.…”

Section: Aggregation Of Huntingtin In and Out Of The Cellsupporting

confidence: 57%

Protein misfolding inside cells: The case of huntingtin and Huntington's disease

Hatters

2008

IUBMB Life

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SummaryHuntington's disease is one of the several neurodegenerative diseases caused by dominant mutations that expand the number of glutamine codons within an existing poly-glutamine (polyQ) repeat sequence of a gene. An expanded polyQ sequence in the huntingtin gene is known to cause the huntingtin protein to aggregate and form intracellular inclusions as disease progresses. However, the role that polyQ-induced aggregation plays in disease is yet to be fully determined. This review focuses on key questions remaining for how the expanded polyQ sequences affect the aggregation properties of the huntingtin protein and the corresponding effects on cellular machinery. The scope includes the technical challenges that remain for rigorously assessing the effects of aggregation on the cellular machinery.2008 IUBMB IUBMB Life, 60(11): 724-728, 2008

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Perillaldehyde alleviates polyQ‐induced neurodegeneration through the induction of autophagy and mitochondrial UPR in Caenorhabditis elegans

Fang,

Liu,

Gao

et al. 2024

BioFactors

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Huntington's disease (HD) is a fatal neurodegenerative disease associated with autophagy disorder and mitochondrial dysfunction. Here, we identified therapeutic potential of perillaldehyde (PAE), a monoterpene compound obtained from Perilla frutescens (L.) Britt., in the Caenorhabditis elegans (C. elegans) model of HD, which included lifespan extension, healthspan improvement, decrease in polyglutamine (polyQ) aggregation, and preservation of mitochondrial network. Further analyses indicated that PAE was able to induce autophagy and mitochondrial unfolded protein reaction (UPRmt) activation and positively regulated expression of associated genes. In lgg‐1 RNAi C. elegans or C. elegans with UPRmt‐related genes knockdown, the effects of PAE treatment on polyQ aggregation or rescue polyQ‐induced toxicity were attenuated, suggesting that its neuroprotective activity depended on autophagy and UPRmt. Moreover, we found that pharmacological and genetic activation of UPRmt generally protected C. elegans from polyQ‐induced cytotoxicity. Finally, PAE promoted serotonin synthesis by upregulating expression of TPH‐1, and serotonin synthesis and neurosecretion were required for PAE‐mediated UPRmt activation and its neuroprotective activity. In conclusion, PAE is a potential therapy for polyQ‐related diseases including HD, which is dependent on autophagy and cell‐non‐autonomous UPRmt activation.

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Modeling Polyglutamine Pathogenesis in C. elegans

Cited by 84 publications

References 72 publications

Dictyostelium discoideum has a highly Q/N-rich proteome and shows an unusual resilience to protein aggregation

Dictyostelium discoideum has a highly Q/N-rich proteome and shows an unusual resilience to protein aggregation

Protein misfolding inside cells: The case of huntingtin and Huntington's disease

Perillaldehyde alleviates polyQ‐induced neurodegeneration through the induction of autophagy and mitochondrial UPR in Caenorhabditis elegans

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