Tali Gidalevitz

Bio: Tali Gidalevitz is an academic researcher from Drexel University. The author has contributed to research in topics: Endoplasmic reticulum & Unfolded protein response. The author has an hindex of 15, co-authored 26 publications receiving 1994 citations. Previous affiliations of Tali Gidalevitz include University of Chicago & Northwestern University.

Progressive Disruption of Cellular Protein Folding in Models of Polyglutamine Diseases

Abstract: Numerous human diseases are associated with the chronic expression of misfolded and aggregation-prone proteins. The expansion of polyglutamine residues in unrelated proteins is associated with the early onset of neurodegenerative disease. To understand how the presence of misfolded proteins leads to cellular dysfunction, we employed Caenorhabditis elegans polyglutamine aggregation models. Here, we find that polyglutamine expansions disrupted the global balance of protein folding quality control, resulting in the loss of function of diverse metastable proteins with destabilizing temperature-sensitive mutations. In turn, these proteins, although innocuous under normal physiological conditions, enhanced the aggregation of polyglutamine proteins. Thus, weak folding mutations throughout the genome can function as modifiers of polyglutamine phenotypes and toxicity.

The Stress of Protein Misfolding: From Single Cells to Multicellular Organisms

Abstract: Organisms survive changes in the environmentbyaltering their rates of metabolism, growth, and reproduction. At the same time, the system must ensure the stabilityand functionalityof its macromolecules. Fluctuations in the environment are sensed by highly conserved stress responses and homeostatic mechanisms, and of these, the heat shock response (HSR) represents an essential response to acute and chronic proteotoxic damage. However, unlike the strategies employed to maintain the integrity of the genome, protection of the proteome mustbetailoredtoaccommodatethenormalfluxofnonnativeproteinsandthedifferencesin protein composition between cells, and among individuals. Moreover, adult cells are likely to have significant differences in the rates of synthesis and clearance that are influenced by intrinsicerrorsinproteinexpression,geneticpolymorphisms,andfluctuationsinphysiological and environmental conditions. Here, we will address how protein homeostasis (proteostasis) is achieved at the level of the cell and organism, and how the threshold of the stress response is set to detect and combat protein misfolding. For metazoans, the requirement forcoordinated function and growth imposes additional constraints on the detection, signaling,andresponsetomisfolding,andrequiresthattheHSRisintegratedintovariousaspectsof organismal physiology, such as lifespan. This is achieved by hierarchical regulation of heat shock factor 1 (HSF1) by the metabolic state of the cell and centralized neuronal control that could allow optimal resource allocation between cells and tissues. We will examine how protein folding quality control mechanisms in individual cells may be integrated into a multicellular level of control, and further, even custom-designed to support individual variability and impose additional constraints on evolutionary adaptation.

Destabilizing Protein Polymorphisms in the Genetic Background Direct Phenotypic Expression of Mutant SOD1 Toxicity

Abstract: Genetic background exerts a strong modulatory effect on the toxicity of aggregation-prone proteins in conformational diseases. In addition to influencing the misfolding and aggregation behavior of the mutant proteins, polymorphisms in putative modifier genes may affect the molecular processes leading to the disease phenotype. Mutations in SOD1 in a subset of familial amyotrophic lateral sclerosis (ALS) cases confer dominant but clinically variable toxicity, thought to be mediated by misfolding and aggregation of mutant SOD1 protein. While the mechanism of toxicity remains unknown, both the nature of the SOD1 mutation and the genetic background in which it is expressed appear important. To address this, we established a Caenorhabditis elegans model to systematically examine the aggregation behavior and genetic interactions of mutant forms of SOD1. Expression of three structurally distinct SOD1 mutants in C. elegans muscle cells resulted in the appearance of heterogeneous populations of aggregates and was associated with only mild cellular dysfunction. However, introduction of destabilizing temperature-sensitive mutations into the genetic background strongly enhanced the toxicity of SOD1 mutants, resulting in exposure of several deleterious phenotypes at permissive conditions in a manner dependent on the specific SOD1 mutation. The nature of the observed phenotype was dependent on the temperature-sensitive mutation present, while its penetrance reflected the specific combination of temperature-sensitive and SOD1 mutations. Thus, the specific toxic phenotypes of conformational disease may not be simply due to misfolding/aggregation toxicity of the causative mutant proteins, but may be defined by their genetic interactions with cellular pathways harboring mildly destabilizing missense alleles.

Protein Homeostasis in Models of Aging and Age-Related Conformational Disease

Abstract: The stability of the proteome is crucial to the health of the cell, and contributes significantly to the lifespan of the organism. Aging and many age-related diseases have in common the expression of misfolded and damaged proteins. The chronic expression of damaged proteins during disease can have devastating consequences on protein homeostasis (proteostasis), resulting in disruption of numerous biological processes. This chapter discusses our current understanding of the various contributors to protein misfolding, and the mechanisms by which misfolding, and accompanied aggregation/toxicity, is accelerated by stress and aging. Invertebrate models have been instrumental in studying the processes related to aggregation and toxicity of disease-associated proteins and how dysregulation of proteostasis leads to neurodegenerative diseases of aging.

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

Abstract: 抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

Molecular chaperones in protein folding and proteostasis

Abstract: Most proteins must fold into defined three-dimensional structures to gain functional activity. But in the cellular environment, newly synthesized proteins are at great risk of aberrant folding and aggregation, potentially forming toxic species. To avoid these dangers, cells invest in a complex network of molecular chaperones, which use ingenious mechanisms to prevent aggregation and promote efficient folding. Because protein molecules are highly dynamic, constant chaperone surveillance is required to ensure protein homeostasis (proteostasis). Recent advances suggest that an age-related decline in proteostasis capacity allows the manifestation of various protein-aggregation diseases, including Alzheimer's disease and Parkinson's disease. Interventions in these and numerous other pathological states may spring from a detailed understanding of the pathways underlying proteome maintenance.

Adapting proteostasis for disease intervention.

Abstract: The protein components of eukaryotic cells face acute and chronic challenges to their integrity. Eukaryotic protein homeostasis, or proteostasis, enables healthy cell and organismal development and aging and protects against disease. Here, we describe the proteostasis network, a set of interacting activities that maintain the health of proteome and the organism. Deficiencies in proteostasis lead to many metabolic, oncological, neurodegenerative, and cardiovascular disorders. Small-molecule or biological proteostasis regulators that manipulate the concentration, conformation, quaternary structure, and/or the location of protein(s) have the potential to ameliorate some of the most challenging diseases of our era.

mTOR Signaling in Growth, Metabolism, and Disease

Abstract: The mechanistic target of rapamycin (mTOR) coordinates eukaryotic cell growth and metabolism with environmental inputs, including nutrients and growth factors. Extensive research over the past two decades has established a central role for mTOR in regulating many fundamental cell processes, from protein synthesis to autophagy, and deregulated mTOR signaling is implicated in the progression of cancer and diabetes, as well as the aging process. Here, we review recent advances in our understanding of mTOR function, regulation, and importance in mammalian physiology. We also highlight how the mTOR signaling network contributes to human disease and discuss the current and future prospects for therapeutically targeting mTOR in the clinic.

The amyloid state and its association with protein misfolding diseases

Abstract: The phenomenon of protein aggregation and amyloid formation has become the subject of rapidly increasing research activities across a wide range of scientific disciplines. Such activities have been stimulated by the association of amyloid deposition with a range of debilitating medical disorders, from Alzheimer's disease to type II diabetes, many of which are major threats to human health and welfare in the modern world. It has become clear, however, that the ability to form the amyloid state is more general than previously imagined, and that its study can provide unique insights into the nature of the functional forms of peptides and proteins, as well as understanding the means by which protein homeostasis can be maintained and protein metastasis avoided.