Website Edition: August/September 2009

The Stress of Misfolded Proteins in Aging and Neurodegenerative Disease

By Richard I. Morimoto, PhD
Northwestern University
Evanston, IL. USA

Watch the C. David Marsden lecture delivered by Dr. Morimoto at the 13th International Congress of Parkinson's Disease and Movement Disorders in Paris here.


Aging and stress, stress and aging - a pair of ominous human conditions that affect the quality of life. When events go awry, molecular events take place that, over time, can lead to neurodegenerative disease. At the root of the problem is a fundamental process: that of protein folding and quality control. Proteins are essential products of gene expression and provide much of the shape and functionality of the cell, consequently their synthesis, folding, assembly, translocation, and clearance is essential for the health of the cell and organism. However, when cells are exposed to environmental and physiological stress or when mutant and damaged proteins are chronically expressed, this can lead to cellular dysfunction and disease. The integrity of the proteome is governed by protein homeostasis, or proteostasis, the cellular process that monitors the life of proteins.

Protein misfolding and aggregation are widely implicated in the pathology of many age-associated diseases including Huntington's disease (HD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and Parkinson's disease (PD). For each of these gain-of-function diseases, expression of Huntingtin (Htt), Aβ, mutant SOD1 or α-synuclein, respectively, results in the expression of protein aggregates that alters the subcellular distribution of essential proteins such as chaperones, interferes with degradation of proteasome substrates, and compromises the folding and stability of other proteins that are conformationally challenged. We have proposed that cellular dysfunction observed in protein misfolding disease, is initiated when aggregation-prone proteins are expressed, and cause the global disruption of cellular protein homeostasis, by interfering with the capacity of the proteostasis network.

The long-term health of the proteome depends upon the ability of the proteostasis network to respond to the chronic expression of misfolded proteins and to prevent the age-dependent accumulation of damage. These events are regulated by proteostasis networks that are comprised of molecular chaperones, degradation machineries, and the cytoprotective stress responses such as the heat shock response (HSR), and the unfolded protein response (UPR) that sense the expression of damaged proteins. For example, the HSR enables the cell to adjust the expression of chaperones and other cytoprotective genes under proteotoxic conditions to ensure stress survival, recovery, and adaptation. At the molecular level, this occurs by the transcriptional regulation of HS genes, proportional to the intensity, duration, and type of stress, and the metabolic state of the cell. The expression of HS genes and the HSR is regulated by a family of heat shock transcription factors (HSFs) that are constitutively expressed and maintained in an inert, stress sensing state, and activated to a transcriptionally active state by a wide range of proteotoxic stress signals.

Because the biology of protein folding and the necessity to manage the load of misfolded species is essential to all life forms, many notable insights have been provided by studies of genetic model systems such as the yeast Saccharomyces cerevisiae and the invertebrates Caenorhabditis elegans and Drosophila melanogaster. For example, using a C. elegans model of disease, we have identified multiple conserved factors that determine the cellular toxicity of mutant Huntington; the length of the mutant polyglutamine repeat and age-dependent aggregation (substantive expansion causes disease in humans), the importance of lifespan regulating pathways in proteostasis, and the essential role of the stress sensing transcription factor, HSF1, at the cellular and organismal level to control the level of molecular chaperones. The idea that the molecular determinants of longevity might influence polyglutamine-mediated toxicity is supported by observations that the time until pathology develops days in C. elegans, weeks in Drosophila, months in mice, and years in humans correlates approximately with the lifespan of the organism.

The tendency of disease-associated aggregation-prone proteins to misfold and aggregate is strongly influenced by aging. The accumulation of damaged proteins is a well-established marker of aging, and we have shown that this disruption of proteostasis is further amplified during aging. We have shown that certain lifespan enhancing pathways such as the insulin-like signaling (ILS) pathway are potent modifiers of proteostasis, and can suppress protein aggregation and toxicity. Moreover, ILS-dependent extension of lifespan requires the FOXO transcription factor, DAF-16, and HSF1 to influence lifespan. HSF1 is also regulated by the NAD-dependent sirtuin, SIRT1, whose activity is diminished during aging and enhanced by caloric restriction. Stimulation of HSF1 by SIRT1, in turn, maintains HSF1 in an active functional state bound to promoters for chaperone genes. In addition to this multi-layered regulatory control of chaperone expression at the cellular level, the HSR at the organismal level, in C. elegans, is regulated by the AFD thermosensory neurons that sense temperature. Animals deficient in thermosensory neurons do not activate the HSR revealing that the expression of HS genes is regulated by cell non-autonomous control. These results reveal that the HS response is organized at the systems level of the organism to sense the stress signal through active neuronal activity, and together with the metabolic state, sets the proteostasis network to ensure stability of the proteome and the health of the organism.