PolyQ disease: misfiring of a developmental cell death program?

Blum, Elyse S.; Schwendeman, Andrew R.; Shaham, Shai

doi:10.1016/j.tcb.2012.11.003

Cited by 52 publications

(35 citation statements)

References 96 publications

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“…In spite of enormous efforts, the HD field has not reached a consensus on this central question, which has remained “stubbornly unclear” 54 . A variety of mechanisms, many involving the mediation of protein aggregates, have been suggested 3, 55–62 , and work continues to sort out this experimentally complex issue.…”

Section: Discussionmentioning

confidence: 99%

d-Polyglutamine Amyloid Recruits l-Polyglutamine Monomers and Kills Cells

Kar

Arduini

Drombosky

et al. 2014

Journal of Molecular Biology

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Polyglutamine (polyQ) amyloid fibrils are observed in disease tissue and have been implicated as toxic agents responsible for neurodegeneration in expanded CAG repeat diseases like Huntington’s disease (HD). Despite intensive efforts, the mechanism of amyloid toxicity remains unknown. As a novel approach to probing polyQ toxicity, we investigate here how some cellular and physical properties of polyQ amyloid vary with the chirality of the glutamine residues in the polyQ. We challenged PC12 cells with small amyloid fibrils composed of either L- or D-polyQ peptides and found that D-fibrils are as cytotoxic as L-fibrils. We also found using fluorescence microscopy that both aggregates effectively seed the aggregation of cell-produced L-polyQ proteins, suggesting a surprising lack of stereochemical restriction in seeded elongation of polyQ amyloid. To investigate this effect further, we studied chemically synthesized D- and L-polyQ in vitro. We found that, as expected, D-polyQ monomers are not recognized by proteins that recognize L-polyQ monomers. However, amyloid fibrils prepared from D-polyQ peptides can efficiently seed the aggregation of L-polyQ monomers in vitro, and vice versa. This result is consistent with our cell results on polyQ recruitment, but is inconsistent with previous literature reports on the chiral specificity of amyloid seeding. This chiral cross-seeding can be rationalized by a model for seeded elongation featuring a “rippled β-sheet” interface between seed fibril and docked monomers of opposite chirality. The lack of chiral discrimination in polyQ amyloid cytotoxicity is consistent with several toxicity mechanisms, including recruitment of cellular polyQ proteins.

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Section: Discussionmentioning

confidence: 99%

d-Polyglutamine Amyloid Recruits l-Polyglutamine Monomers and Kills Cells

Kar

Arduini

Drombosky

et al. 2014

Journal of Molecular Biology

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“…However, the other examples of ovarian PCD can occur in the absence of caspase activity and provide a valuable opportunity to decipher non-apoptotic cell death pathways. The contribution of non-apoptotic cell death to disease in humans has become increasingly appreciated, inspiring several recent reviews and conferences [74–76]. …”

Section: Discussionmentioning

confidence: 99%

Diversity of cell death pathways: insight from the fly ovary

Jenkins

Timmons

McCall

2013

Trends in Cell Biology

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Multiple types of cell death exist including necrosis, apoptosis, and autophagic cell death. The Drosophila ovary provides a valuable model to study the diversity of cell death modalities, and we review recent progress to elucidate these pathways. At least five distinct types of cell death occur in the ovary, and we focus on two that have been studied extensively. Cell death of mid-stage egg chambers uses a novel caspase-dependent pathway that involves autophagy, and triggers phagocytosis by surrounding somatic epithelial cells. For every egg, fifteen germline nurse cells undergo developmental programmed cell death, which occurs independently of most known cell death genes. These forms of cell death are strikingly similar to cell death observed in the germline of other organisms.

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“…S6E), presumably because a single point mutation in [CAG] n can form a stop codon only in this frame. Natural selection might also contribute to the demise of the polyQ frame because polyglutamines from expanding [CAG] n are associated with protein aggregation, toxicity, and pathologies (Blum et al 2013). Importantly, point mutations in other frames of [CAG] n are either silent or cause amino acid changes, thus leading to diversification of the originally homopolymeric amino acid chain.…”

Section: Wwwgenomeorgmentioning

confidence: 99%

Long terminal repeats power evolution of genes and gene expression programs in mammalian oocytes and zygotes

et al. 2017

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Retrotransposons are "copy-and-paste" insertional mutagens that substantially contribute to mammalian genome content. Retrotransposons often carry long terminal repeats (LTRs) for retrovirus-like reverse transcription and integration into the genome. We report an extraordinary impact of a group of LTRs from the mammalian endogenous retrovirus-related ERVL retrotransposon class on gene expression in the germline and beyond. In mouse, we identified more than 800 LTRs from ORR1, MT, MT2, and MLT families, which resemble mobile gene-remodeling platforms that supply promoters and first exons. The LTR-mediated gene remodeling also extends to hamster, human, and bovine oocytes. The LTRs function in a stagespecific manner during the oocyte-to-embryo transition by activating transcription, altering protein-coding sequences, producing noncoding RNAs, and even supporting evolution of new protein-coding genes. These functions result, for example, in recycling processed pseudogenes into mRNAs or lncRNAs with regulatory roles. The functional potential of the studied LTRs is even higher, because we show that dormant LTR promoter activity can rescue loss of an essential upstream promoter. We also report a novel protein-coding gene evolution-D6Ertd527e-in which an MT LTR provided a promoter and the 5

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PolyQ disease: misfiring of a developmental cell death program?

Cited by 52 publications

References 96 publications

d-Polyglutamine Amyloid Recruits l-Polyglutamine Monomers and Kills Cells

d-Polyglutamine Amyloid Recruits l-Polyglutamine Monomers and Kills Cells

Diversity of cell death pathways: insight from the fly ovary

Long terminal repeats power evolution of genes and gene expression programs in mammalian oocytes and zygotes

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