Protein Misfolding in Aging and Neurodegenerative Disease

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 or enhance the risk of neurodegenerative disease. At the root of problem is a fundamental process common to all cells, protein folding. When proteins misbehave and misfold, however, they can adopt altered states that cause diseases of protein conformation including the neurodegenerative diseases Huntington's disease, Amyotrophic Lateral Sclerosis, Alzheimer's disease, Parkinson's disease, and Creutzfeld-Jacob. For each, a hallmark of the disease is the appearance of misfolded and mutant proteins (Huntingtin, superoxide dismutase, amyloid b peptide, a-synuclein) and associated toxicity. How these proteotoxic species form, the processes that determine their persistence or clearance, and the molecular basis of their toxicity are critical to understanding the disease mechanism. Our studies address how misfolded proteins cause cell stress and interfere with cellular function, the identification and characterization of cellular machineries in protein homeostasis that recognize and detoxify misfolded proteins, the basis of cell-type specific neurotoxicity, and the identification of genes that regulate lifespan as a modulators of these events. The identification of the chaperome network that determines protein quality control thus forms the basis for a new class of therapeutics for neurodegenerative diseases of aging.