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Báo cáo khoa học: G1–Molecular Chaperones

Misfolded proteins, aggregates, and inclusion bodies are hall-marks of the cytopathology of neurodegenerative disorders including Huntington’s disease, Amyotropic lateral sclerosis, Parkinson’s disease, Prion diseases, and Alzheimer’s disease. The appearance of proteins with altered folded states is regula-ted by the protein folding quality control machinery and age-dependent. We have identified an unexpected molecular link between metabolic state, accumulation of damaged proteins, the heat-shock response and chaperones, and longevity | Abstracts G1-Molecular Chaperones G1-001 Stress and misfolded proteins modulators of neurodegenerative diseases and longevity R. I. Morimoto J. Morley H. Brignull S. Garcia K. Richter and C. Kaiser Laboratory of Biochemistry Molecular Biology Department of Biochemistry Molecular Biology and Cell Biology Northwestern University Evanston IL USA. E-mail r-morimoto@northwestern.edu Misfolded proteins aggregates and inclusion bodies are hallmarks of the cytopathology of neurodegenerative disorders including Huntington s disease Amyotropic lateral sclerosis Parkinson s disease Prion diseases and Alzheimer s disease. The appearance of proteins with altered folded states is regulated by the protein folding quality control machinery and agedependent. We have identified an unexpected molecular link between metabolic state accumulation of damaged proteins the heat-shock response and chaperones and longevity. Mutations age-1 daf-2 in the insulin-like signaling ILS pathway in C. elegans leading to longevity results in the suppression of polyglutamine toxicity and aggregate formation. Because overexpression of HSF-1 a known regulator of chaperone networks and quality control was also shown to suppress polyglutamine aggregation we examined whether HSF-1-regulated lifespan. Downregulation of hsf-1 by RNAi in neurons and muscle cells suppressed longevity which reveals a new molecular link between longevity and stress resistance. To identify other modifiers of protein quality control we screened transgenic polyglu-tamine-expressing strains using genome-wide RNAi to identify genes that regulate polyglutamine aggregation. Nearly 200 genes were identified defining a protein quality control proteome corresponding to five principal classes of polyglutamine regulators genes involved in RNA metabolism protein synthesis protein folding protein degradation and those involved in protein trafficking. We propose that each of these classes represents a molecular machine that collectively .