Susan Lindquist

Susan Lindquist
Whitehead Institute for Biomedical Research · Department of Biology

About

386
Publications
44,339
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55,825
Citations
Citations since 2016
48 Research Items
21149 Citations
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201620172018201920202021202205001,0001,5002,0002,5003,000
201620172018201920202021202205001,0001,5002,0002,5003,000
201620172018201920202021202205001,0001,5002,0002,5003,000

Publications

Publications (386)
Preprint
In neurodegenerative proteinopathies, intracellular inclusions are histopathologically and ultrastructurally heterogeneous but the significance of this heterogeneity is unclear. Patient- derived iPSC models, while promising for disease modeling, do not form analogous inclusions in a reasonable timeframe and suffer from limited tractability and scal...
Article
Heat shock factor 1 (HSF1) is well known for its role in the heat shock response (HSR), where it drives a transcriptional program comprising heat shock protein (HSP) genes, and in tumorigenesis, where it drives a program comprising HSPs and many noncanonical target genes that support malignancy. Here, we find that HSF2, an HSF1 paralog with no subs...
Article
Eukaryotic initiation factor 4A (eIF4A), the enzymatic core of the eIF4F complex essential for translation initiation, plays a key role in the oncogenic reprogramming of protein synthesis, and thus is a putative therapeutic target in cancer. As important component of its anticancer activity, inhibition of translation initiation can alleviate oncoge...
Article
The E4 allele of the apolipoprotein E gene ( APOE ) has been established as a genetic risk factor for many diseases including cardiovascular diseases and Alzheimer’s disease (AD), yet its mechanism of action remains poorly understood. APOE is a lipid transport protein, and the dysregulation of lipids has recently emerged as a key feature of several...
Article
Full-text available
The ε4 allele of apolipoprotein E (APOE4) is a genetic risk factor for many diseases, including late-onset Alzheimer's disease (AD). We investigate the cellular consequences of APOE4 in human iPSC-derived astrocytes, observing an endocytic defect in APOE4 astrocytes compared with their isogenic APOE3 counterparts. Given the evolutionarily conserved...
Article
Full-text available
The heat shock protein 90 (Hsp90) chaperone functions as a protein-folding buffer and plays a role promoting the evolution of new heritable traits. To better understand how Hsp90 can affect mRNA translation, we screen more than 1,600 factors involved in mRNA regulation for physical interactions with Hsp90 in human cells. The mRNA binding protein CP...
Article
Full-text available
The mechanisms by which cells adapt to proteotoxic stress are largely unknown, but are key to understanding how tumor cells, particularly in vivo, are largely resistant to proteasome inhibitors. Analysis of cancer cell lines, mouse xenografts and patient-derived tumor samples all showed an association between mitochondrial metabolism and proteasome...
Article
Full-text available
An amendment to this paper has been published and can be accessed via a link at the top of the paper
Article
Purpose: Despite the accumulation of extensive genomic alterations, many cancers fail to be recognized as “foreign” and escape destruction by the host immune system. Immunotherapies designed to address this problem by directly stimulating immune effector cells have led to some remarkable clinical outcomes, but unfortunately, most cancers fail to re...
Article
Full-text available
New strategies are needed to counter the escalating threat posed by drug-resistant fungi. The molecular chaperone Hsp90 affords a promising target because it supports survival, virulence and drug-resistance across diverse pathogens. Inhibitors of human Hsp90 under development as anticancer therapeutics, however, exert host toxicities that preclude...
Article
In Parkinson's disease (PD), α-synuclein (αS) pathologically impacts the brain, a highly lipid-rich organ. We investigated how alterations in αS or lipid/fatty acid homeostasis affect each other. Lipidomic profiling of human αS-expressing yeast revealed increases in oleic acid (OA, 18:1), diglycerides, and triglycerides. These findings were recapit...
Preprint
Full-text available
The heat shock protein 90 (Hsp90) chaperone functions as a protein-folding buffer and plays a unique role promoting the evolution of new heritable traits. To investigate the role of Hsp90 in modulating protein synthesis, we screened more than 1600 proteins involved in mRNA regulation for physical interactions with Hsp90 in human cells. Among the to...
Preprint
The mechanisms used by cancer cells to resist the severe disruption in protein homeostasis caused by proteasome inhibitors remain obscure. Here, we show this resistance correlates with a metabolic shift from glycolysis to oxidative phosphorylation (OXPHOS). Employing small molecule screens, we identified a striking overlap between compounds that pr...
Article
Tyrosine phosphorylation is a key biochemical signal that controls growth and differentiation in multicellular organisms. Saccharomyces cerevisiae and nearly all other unicellular eukaryotes lack intact phosphotyrosine signaling pathways. However, many of these organisms have primitive phosphotyrosine-binding proteins and tyrosine phosphatases, lea...
Article
Aggregates of human islet amyloid polypeptide (IAPP) in the pancreas of patients with type 2 diabetes (T2D) are thought to contribute to β cell dysfunction and death. To understand how IAPP harms cells and how this might be overcome, we created a yeast model of IAPP toxicity. Ste24, an evolutionarily conserved protease that was recently reported to...
Article
Full-text available
The development of effective antifungal therapeutics remains a formidable challenge because of the close evolutionary relationship between humans and fungi. Mitochondrial function may present an exploitable vulnerability because of its differential utilization in fungi and its pivotal roles in fungal morphogenesis, virulence, and drug resistance al...
Article
Full-text available
Significance Calcineurin is an essential Ca ²⁺ -dependent phosphatase in all eukaryotes. Whether calcineurin can be endogenously regulated by factors other than Ca ²⁺ and calmodulin is not known. Using a model of Parkinson's Disease (PD) as a surrogate for high pathophysiological calcineurin activity and employing a shotgun proteomic approach, we s...
Article
Full-text available
Author summary Microbial species do not have control over their environment. In order to survive changes (for example, in temperature, pressure, humidity, or nutrient levels), microbes must either migrate to more habitable locations or adapt to better tolerate the changing environment. Such adaptation is typically thought to come about through chan...
Data
FLO8-dependent migratory benefits of [SWI+] cells. (A) Comparison of migration of [SWI+] and [swi−] cells lacking a functional FLO8 gene, which is required for the expression of Flo1 and Flo11 [12]. (B) Fraction of the total liquid culture (notched bars) or supernatant only (plain bars) that is [SWI+] after 16 hours of growth in YPD or YPD + 5% eth...
Data
[SWI+] pioneers are less fit than [swi−] settler cells. (A) Growth comparison of [swi−] cells (blue) and [SWI+] cells (red) in standard growth media supplemented with glucose, or B) raffinose. Cell density was measured by absorbance at 600 nm every 15 minutes. Numerical data is available from the Dryad Digital Repository: http://dx.doi.org/10.5061/...
Data
Yeast strains used in this study. Each yeast strain used in the study is listed along with its Swi1 prion status, transformed plasmids, and genotype. (XLSX)
Data
Experimental procedure for out-cross ratio measurement. [SWI+] and [swi−] diploid strains were sporulated. Each had the genotype HO+/ho−, where the ho locus was marked with a cassette expressing the green fluorescent protein NeonGreen. A large pool of these spores was diluted into mixed culture with a ho−, selectable, haploid tester strain. After a...
Article
Protein aggregation is a hallmark of many diseases but also underlies a wide range of positive cellular functions. This phenomenon has been difficult to study because of a lack of quantitative and high-throughput cellular tools. Here, we develop a synthetic genetic tool to sense and control protein aggregation. We apply the technology to yeast prio...
Article
α-Synuclein (αS) forms round cytoplasmic inclusions in Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Evidence suggests a physiological function of αS in vesicle trafficking and release. In contrast to earlier tenets, recent work indicates that αS normally exists in cells in a dynamic equilibrium between monomers and tetramers/multim...
Article
Full-text available
The lack of therapies for neurodegenerative diseases arises from our incomplete understanding of their underlying cellular toxicities and the limited number of predictive model systems. It is critical that we develop approaches to identify novel targets and lead compounds. Here, a phenotypic screen of yeast proteinopathy models identified dihydropy...
Article
Significance Self-propagating changes in the conformation of amyloidogenic proteins play vital roles in normal biology and disease. Despite intense research, the architecture of amyloid fibers remains poorly understood. In this work, we used both segmental and specific isotopic labeling schemes in combination with dynamic nuclear polarization (DNP)...
Article
HSP90 acts as a protein-folding buffer that shapes the manifestations of genetic variation in model organisms. Whether HSP90 influences the consequences of mutations in humans, potentially modifying the clinical course of genetic diseases, remains unknown. By mining data for >1,500 disease-causing mutants, we found a strong correlation between redu...
Article
Full-text available
Numerous genes and molecular pathways are implicated in neurodegenerative proteinopathies, but their inter-relationships are poorly understood. We systematically mapped molecular pathways underlying the toxicity of alpha-synuclein (α-syn), a protein central to Parkinson’s disease. Genome-wide screens in yeast identified 332 genes that impact α-syn...
Article
Synucleinopathies, including Parkinson’s disease (PD), are associated with the misfolding and mistrafficking of alpha-synuclein (α-syn). Here, using an ascorbate peroxidase (APEX)-based labeling method combined with mass spectrometry, we defined a network of proteins in the immediate vicinity of α-syn in living neurons to shed light on α-syn functi...
Article
The proteasome is a central regulator of protein homeostasis in all eukaryotes. Targeted pharmaceutical inhibition of the proteasome complex has been implemented as a successful therapeutic strategy to treat several cancers including multiple myeloma. Unfortunately, many of the cancers show intrinsic resistance to proteasome inhibitors, and those t...
Article
Full-text available
Significance In previous work, we used genome-wide screening to uncover a counterintuitive mechanism by which cells can acquire resistance to inhibitors of the proteasome’s catalytic core through experimentally induced imbalances in the composition of its regulatory particle. However, in many cases, mechanisms uncovered in vitro for acquired resist...
Article
Prions are a paradigm-shifting mechanism of inheritance in which phenotypes are encoded by self-templating protein conformations rather than nucleic acids. Here, we examine the breadth of protein-based inheritance across the yeast proteome by assessing the ability of nearly every open reading frame (ORF; ∼5,300 ORFs) to induce heritable traits. Tra...
Article
To cause disease, a microbial pathogen must adapt to the challenges of its host environment. The leading fungal pathogen Candida albicans colonizes nutrient-poor bodily niches, withstands attack from the immune system, and tolerates treatment with azole antifungals, often evolving resistance. To discover agents that block these adaptive strategies,...
Article
Full-text available
Significance Prion proteins provide the best-understood mode for protein-based molecular memory. Since their discovery in mammals, prions have been identified in diverse organisms including fungi, Aplysia , and Drosophila , but not in the plant kingdom. Applying methods we used to uncover yeast prions, we identified nearly 500 Arabidopsis proteins...
Article
Full-text available
In cellular systems, biophysical interactions between macromolecules underlie a complex web of functional interactions. How biophysical and functional networks are coordinated, whether all biophysical interactions correspond to functional interactions, and how such biophysical-versus-functional network coordination is shaped by evolutionary forces...
Article
Heat shock factor 1 (HSF1) is best known as a key sensor of proteotoxic stress, but accumulating evidence also supports a major role for this transcriptional regulator in cancer biology. In a variety of human solid tumor cells, downregulation of HSF1 inhibits growth, induces cell death and limits metastatic potential. In breast cancers, nuclear acc...
Article
Biological processes occur in complex environments containing a myriad of potential interactors. Unfortunately, limitations on the sensitivity of biophysical techniques normally restrict structural investigations to purified systems, at concentrations that are orders of magnitude above endogenous levels. Dynamic nuclear polarization (DNP) can drama...
Data
KBM7 screening hits for MG132 and bortezomib, insertions and p-values. DOI: http://dx.doi.org/10.7554/eLife.08467.016
Data
RNA-seq analysis. DOI: http://dx.doi.org/10.7554/eLife.08467.018
Data
Validation reagents: lentivirus clones, selected shRNAs, antibodies. DOI: http://dx.doi.org/10.7554/eLife.08467.017
Data
Genomics of drug sensitivity in cancer analysis. DOI: http://dx.doi.org/10.7554/eLife.08467.019
Article
The delivery of diagnostic and therapeutic agents to solid tumors is limited by physical transport barriers within tumors, and such restrictions directly contribute to decreased therapeutic efficacy and the emergence of drug resistance. Nanomaterials designed to perturb the local tumor environment with precise spatiotemporal control have demonstrat...
Article
Drugs that act more promiscuously provide fewer routes for the emergence of resistant mutants. This benefit, however, often comes at the cost of serious off-target and dose-limiting toxicities. The classic example is the antifungal amphotericin B (AmB), which has evaded resistance for more than half a century. We report markedly less toxic amphoter...
Article
The emergence of drug resistance is a major limitation of current antimalarials. The discovery of new druggable targets and pathways including those that are critical for multiple life cycle stages of the malaria parasite is a major goal for developing next-generation antimalarial drugs. Using an integrated chemogenomics approach that combined drug...
Article
In the absence of a single preventive or disease-modifying strategy, neurodegenerative diseases are becoming increasingly prevalent in our ageing population. The mechanisms underlying neurodegeneration are poorly understood, making the target-based drug screening strategies that are employed by the pharmaceutical industry fraught with difficulty. H...
Patent
Full-text available
Disclosed are genes that, when overexpressed in cells expressing alpha-synuclein, either suppress or enhance alpha-synuclein mediated cellular toxicity. Compounds that modulate expression of these genes or activity of the encoded proteins can be used to inhibit alpha-synuclein mediated toxicity and used to treat or prevent synucleinopathies such as...
Article
How disease-associated mutations impair protein activities in the context of biological networks remains mostly undetermined. Although a few renowned alleles are well characterized, functional information is missing for over 100,000 disease-associated variants. Here we functionally profile several thousand missense mutations across a spectrum of Me...
Article
The ribosome is centrally situated to sense metabolic states, but whether its activity, in turn, coherently rewires transcriptional responses is unknown. Here, through integrated chemical-genetic analyses, we found that a dominant transcriptional effect of blocking protein translation in cancer cells was inactivation of heat shock factor 1 (HSF1),...
Article
Steadily increasing antifungal drug resistance and persistent high rates of fungal-associated mortality highlight the dire need for the development of novel antifungals. Characterization of inhibitors of one enzyme in the GPI anchor pathway, Gwt1, has generated interest in the exploration of targets in this pathway for further study. Utilizing a ch...
Article
Full-text available
Significance Although hormonal therapies for estrogen receptor-positive (ER+) breast cancer make up the earliest, and arguably most effective, “molecularly targeted” anticancer drugs, continued progress in controlling metastatic disease has been slow. Heterogeneity and the complexity of signaling in advanced cancers have frustrated efforts to preve...
Article
Full-text available
Significance Amyloids, which are protein fiber aggregates, are often associated with neurodegenerative diseases such as Alzheimer’s, but they can also be beneficial, as in yeasts, where they help cells adapt to environmental changes. Intriguingly, the same protein has the ability to aggregate into different fiber forms, known as strains, that gener...
Article
The disheartening results of recent clinical trials for neurodegenerative disease (ND) therapeutics underscore the need for a more comprehensive understanding of the underlying disease biology before effective therapies can be devised. One hallmark of many NDs is a disruption in protein homeostasis. Therefore, investigating the role of protein home...
Article
No disease-modifying therapies are available for synucleinopathies, including Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple systems atrophy (MSA). The lack of therapies has been impeded by a paucity of validated drug targets and problematic cell-based model systems. New approaches are therefore needed to identify genes and...
Article
Jarosz and Lancaster are co-first authors [ GAR <sup>+</sup>] is a protein-based element of inheritance that allows yeast ( Saccharomyces cerevisiae ) to circumvent a hallmark of their biology: extreme metabolic specialization for glucose fermentation. When glucose is present, yeast will not use other carbon sources. [ GAR <sup>+</sup>] allows cel...
Article
In experimental science, organisms are usually studied in isolation, but in the wild, they compete and cooperate in complex communities. We report a system for cross-kingdom communication by which bacteria heritably transform yeast metabolism. An ancient biological circuit blocks yeast from using other carbon sources in the presence of glucose. [ G...