David Ron, Ph. D.
Skirball Institute - New York University School of Medicine

Proteotoxicity and Aging.
Proteins make up a substantial portion of the cell's mass and are involved in most regulated aspects of its activity. They consist of complex polymers of amino acids joined together through peptide bonds. To function, proteins must undergo a folding process that gives them the proper three dimensional structure. Numerous genetic and biochemical observations suggest that proteins that fail to fold properly impair cell function. This process, also referred to as proteotoxicity, is particularly important to the fate of non-renewable cells of long-lived organisms in which malfolded proteins (proteotoxins) can exert their deleterious influence over extended periods of time. The hypothesized contribution of proteotoxins to progressive cellular dysfunction fits our intuitive notion of aging as a time- and use-dependent process. Aging of the human population has led to increased incidence of diseases associated with various forms of proteotoxicity. These include not only the classic examples of the Amyloidoses, Prion disorders, Motor Neuron disease, Alzheimer's disease and various forms of Parkinsonism - in all of which accumulation of abnormal proteins can be readily observed - but also, we hypothesize, other common age-related disorders. For example, in adult-onset Diabetes Mellitus low-level of protein malfolding may contribute, over time, to exhaustion of the insulin-producing cells of the endocrine pancreas. Recent developments in cell biology and pharmacology have rendered the process of proteotoxicity potentially amenable to therapeutic manipulation. Our research program addresses the fundamental biology behind such future interventions.

Our effort will be directed to understanding how cells recognize and respond to malfolded proteins. For technical reasons we will focus on malfolded proteins that accumulate in the cells secretory pathway. We will utilize a simple model organism, the worm C. elegans, to carry out a genetic screen for mutations that impair the ability of worms to deal with proteotoxins. Despite the many dissimilarities between humans and worms, there are strong reasons for believing that both species use similar components for recognizing and dealing with malfolded proteins. Cloning and identification of the genes involved in the worm's response to proteotoxic stress will provide us with insight as to how human cells recognize and respond to the same problem. Like other perturbations in cellular wellbeing, the pathophysiological effects of proteotoxins are likely to be influenced by the complex response to this form of stress. Some of the cellular responses to proteotoxins are likely to be simply adaptive, while others may over-shoot their mark and contribute to the morbid process. For example, activating the cellular apparatus that refolds or degrades malfolded protein is likely to directly reduce proteotoxicity, whereas over-activity of certain other responses may, under certain circumstances, contribute to cell death and dysfunction. A detailed understanding of the response to proteotoxins that emerge in a given physiological setting will help us distinguish between responses that are beneficial and adverse in that setting. Worms bearing mutations that selectively affect specific components of the cellular response to proteotoxic stress will inform us on the physiological significance of the missing adaptation.

The goal of our research is therefore to identify and categorize the responses to proteotoxic stress in terms of their potential to serve as targets for therapies that may, one day, impact on diseases caused by proteotoxicity. Phrased in the simplest of terms, we would like to know which responses to augment and which responses to inhibiting in a given clinical setting.

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