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167 results on '"Lindquist, Susan L."'

21. Structural insights into a yeast prion illuminate nucleation and strain diversity

Author

Krishnan, Rajaraman and Lindquist, Susan L.

Subjects
Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Author(s): Rajaraman Krishnan [1]; Susan L. Lindquist (corresponding author) [1] Prion proteins share an unusual property: they adopt distinct functional and conformational states that self-perpetuate through protein-conformational chain reactions [1, [...]

Published
2005
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22. Epigenetic regulation of translation reveals hidden genetic variation to produce complex traits

Author

True, Heather L., Berlin, Ilana, and Lindquist, Susan L.

Subjects
Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Author(s): Heather L. True [2]; Ilana Berlin; Susan L. Lindquist (corresponding author) Phenotypic plasticity and the exposure of hidden genetic variation both affect the survival and evolution of new traits [...]

Published
2004
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23. Effects of Q/N-rich, polyQ, and non-polyQ amyloids on the de novo formation of the [PS[I.sup.+]] prion in yeast and aggregation of Sup35 in vitro

Author

Derkatch, Irina L., Uptain, Susan M., Outeiro, Tiago F., Krishnan, Rajaraman, Lindquist, Susan L., and Liebman, Susan W.

Subjects
Prions -- Research, Science and technology
Abstract

Prions are infectious protein conformations that are generally ordered protein aggregates. In the absence of prions, newly synthesized molecules of these same proteins usually maintain a conventional soluble conformation. However, prions occasionally arise even without a homologous prion template. The conformational switch that results in the de novo appearance of yeast prions with glutamine/aspargine (Q/N)-rich prion domains (e.g., [PS[I.sup.+]]), is promoted by heterologous prions with a similar domain (e.g., [RN[Q.sup.+]], also known as [PI[N.sup.+]]), or by overexpression of proteins with prion-like Q-, N-, or Q/N-rich domains. This finding led to the hypothesis that aggregates of heterologous proteins provide an imperfect template on which the new prion is seeded. Indeed, we show that newly forming Sup35 and preexisting Rnq1 aggregates always colocalize when [PS[I.sup.+]] appearance is facilitated by the [RN[Q.sup.+]] prion, and that Rnq1 fibers enhance the in vitro formation of fibers by the prion domain of Sup35 (NM). The proteins do not however form mixed, interdigitated aggregates. We also demonstrate that aggregating variants of the polyQ-containing domain of huntingtin promote the de novo conversion of Sup35 into [PS[I.sup.+]]; whereas nonaggregating variants of huntingtin and aggregates of non-polyQ amyloidogenic proteins, transthyretin, [alpha]-synuclein, and synphilin do not. Furthermore, transthyretin and [alpha]-synuclein amyloids do not facilitate NM aggregation in vitro, even though in [PS[I.sup.+]] cells NM and transthyretin aggregates also occasionally colocalize. Our data, especially the in vitro reproduction of the highly specific heterologous seeding effect, provide strong support for the hypothesis of cross-seeding in the spontaneous initiation of prion states.

Published
2004

32. Strong Unity, Rich Diversity: The Human Genome

Author

LINDQUIST, SUSAN L.

Subjects
Human genome -- Social aspects, Genomes -- Research -- Social aspects, Genetic engineering -- Social aspects -- Research, Human genome -- Social aspects, Education, Ethnic, cultural, racial issues/studies, Social aspects, Research
Abstract

Without a doubt, this is the most important and most wondrous map ever produced by humankind.' Thus did President Clinton describe the announcement, at a White House ceremony June 26, [...]

Published
2000

33. A Chaperone Pathway in Protein Disaggregation: HSP26 ALTERS THE NATURE OF PROTEIN AGGREGATES TO FACILITATE REACTIVATION BY HSP104S

Author

Cashikar, Anil G., Duennwald, Martin, and Lindquist, Susan L.

Subjects
Saccharomyces cerevisiae Proteins, Solubility, Mutation, Saccharomyces cerevisiae, Article, Heat-Shock Proteins, Heat-Shock Response, Molecular Chaperones, Sequence Deletion
Abstract

Cellular protein folding is challenged by environmental stress and aging, which lead to aberrant protein conformations and aggregation. One way to antagonize the detrimental consequences of protein misfolding is to reactivate vital proteins from aggregates. In the yeast Saccharomyces cerevisiae, Hsp104 facilitates disaggregation and reactivates aggregated proteins with assistance from Hsp70 (Ssa1) and Hsp40 (Ydj1). The small heat shock proteins, Hsp26 and Hsp42, also function in the recovery of misfolded proteins and prevent aggregation in vitro, but their in vivo roles in protein homeostasis remain elusive. We observed that after a sublethal heat shock, a majority of Hsp26 becomes insoluble. Its return to the soluble state during recovery depends on the presence of Hsp104. Further, cells lacking Hsp26 are impaired in the disaggregation of an easily assayed heat-aggregated reporter protein, luciferase. In vitro, Hsp104, Ssa1, and Ydj1 reactivate luciferase:Hsp26 co-aggregates 20-fold more efficiently than luciferase aggregates alone. Small Hsps also facilitate the Hsp104-mediated solubilization of polyglutamine in yeast. Thus, Hsp26 renders aggregates more accessible to Hsp104/Ssa1/Ydj1. Small Hsps partially suppress toxicity, even in the absence of Hsp104, potentially by sequestering polyglutamine from toxic interactions with other proteins. Hence, Hsp26 plays an important role in pathways that defend cells against environmental stress and the types of protein misfolding seen in neurode-generative disease.

Published
2005

34. Prion protein gene polymorphisms in Saccharomyces cerevisiae

Author

Resende, Catarina, Outeiro, Tiago F., Sands, Laina, Lindquist, Susan L., and Tuite, Mick F.

Abstract

The yeast Saccharomyces cerevisiae genome encodes several proteins that, in laboratory strains, can take up a stable, transmissible prion form. In each case, this requires the Asn/Gln-rich prion-forming domain (PrD) of the protein to be intact. In order to further understand the evolutionary significance of this unusual property, we have examined four different prion genes and their corresponding PrDs, from a number of naturally occurring strains of S. cerevisiae. In 4 of the 16 strains studied we identified a new allele of the SUP35 gene (SUP35delta19) that contains a 19-amino-acid deletion within the N-terminal PrD, a deletion that eliminates the prion property of Sup35p. In these strains a second prion gene, RNQ1, was found to be highly polymorphic, with eight different RNQ1 alleles detected in the six diploid strains studied. In contrast, for one other prion gene (URE2) and the sequence of the NEW1 gene encoding a PrD, no significant degree of DNA polymorphism was detected. Analysis of the naturally occurring alleles of RNQ1 and SUP35 indicated that the various polymorphisms identified were associated with DNA tandem repeats (6, 12, 33, 42 or 57 bp) within the coding sequences. The expansion and contraction of DNA repeats within the RNQ1 gene may provide an evolutionary mechanism that can ensure rapid change between the [PRION+] and [prion-] states.

Published
2003

35. Interactions among alpha-synuclein, dopamine, and biomembranes: some clues for understanding neurodegeneration in Parkinson's disease

Author

Rochet, Jean-Christophe, Outeiro, Tiago Fleming, Conway, Kelly A., Ding, Tomas T., Volles, Michael J., Lashuel, Hilal A., Bieganski, Robert M., Lindquist, Susan L., Lansbury, Peter T., Rochet, Jean-Christophe, Outeiro, Tiago Fleming, Conway, Kelly A., Ding, Tomas T., Volles, Michael J., Lashuel, Hilal A., Bieganski, Robert M., Lindquist, Susan L., and Lansbury, Peter T.

Abstract

Parkinson's disease (PD) is a neurologic disorder resulting from the loss of dopaminergic neurons in the brain. Two lines of evidence suggest that the protein alpha-synuclein plays a role in the pathogenesis of PD: Fibrillar alpha-synuclein is a major component of Lewy bodies in diseased neurons, and two mutations in alpha-synuclein are linked to early-onset disease. Accordingly, the fibrillization of alpha-synuclein is proposed to contribute to neurodegeneration in PD. In this report, we provide evidence that oligomeric intermediates of the alpha-synuclein fibrillization pathway, termed protofibrils, might be neurotoxic. Analyses of protofibrillar alpha-synuclein by atomic force microscopy and electron microscopy indicate that the oligomers consist of spheres, chains, and rings. alpha-Synuclein protofibrils permeabilize synthetic vesicles and form pore-like assemblies on the surface of brain-derived vesicles. Dopamine reacts with alpha-synuclein to form a covalent adduct that slows the conversion of protofibrils to fibrils. This finding suggests that cytosolic dopamine in dopaminergic neurons promotes the accumulation of toxic alpha-synuclein protofibrils, which might explain why these neurons are most vulnerable to degeneration in PD. Finally, we note that aggregation of alpha-synuclein likely occurs via different mechanisms in the cell versus the test tube. For example, the binding of alpha-synuclein to cellular membranes might influence its self-assembly. To address this point, we have developed a yeast model that might enable the selection of random alpha-synuclein mutants with different membrane-binding affinities. These variants might be useful to test whether membrane binding by alpha-synuclein is necessary for neurodegeneration in transgenic animal models of PD.

Published
2009
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37. Prion Protein is Expressed on Long-term Repopulating Hematopoietic Stem Cells and is Necessary for their Self-renewal

Author

Lodish, Harvey F., Zhang, Cheng Cheng, Steele, Andrew D., Lindquist, Susan L., Lodish, Harvey F., Zhang, Cheng Cheng, Steele, Andrew D., and Lindquist, Susan L.

Abstract

We show that the prion protein (PrP) is expressed on the surface of bone marrow cell populations enriched in long-term repopulating hematopoietic stem cells. Affinity purification of the PrP-positive and PrP-negative fractions from these populations, followed by competitive reconstitution assays, show that all long-term repopulating hematopoietic stem cells express PrP. Hematopoietic stem cells from PrP null bone marrow exhibit impaired self-renewal in serial competitive transplantation experiments, and premature exhaustion when exposed to cell cycle-specific myelotoxic injury. Therefore, PrP is a novel marker for hematopoietic stem cells and regulates their self-renewal., Singapore-MIT Alliance (SMA)

Published
2004

46. Maintenance and inheritance of yeast prions

Author

Tuite, Mick F., Lindquist, Susan L., Tuite, Mick F., and Lindquist, Susan L.

Abstract

The unusual genetic behaviour of two yeast extrachromosomal elements [PSI] and [URE3] is entirely consistent with a prion-like mechanism of inheritance involving an autocatalytic alteration in the conformation of a normal cellular protein. In the case of both yeast determinants the identity of the underlying cellular prion protein is known. The discovery that the molecular chaperone Hsp104 is essential for the establishment and maintenance of the [PSI] determinant provides an explanation for several aspects of the puzzling genetic behaviour of these determinants. What remains to be explained is whether these determinants represent 'disease states' of yeast or represent the first examples of a unique mechanism for producing a heritable change in phenotype without an underlying change in genotype.

Published
1996

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