Protein misfolding and human disease.
Protein misfolding is a common event in living cells. In young and healthy cells, the misfolded protein load is disposed of by protein quality control (PQC) systems. In aging cells and in cells from certain individuals with genetic diseases, the load may overwhelm the PQC capacity, resulting in accumulation of misfolded proteins. Dependent on the properties of the protein and the efficiency of the PQC systems, the accumulated protein may be degraded or assembled into toxic oligomers and aggregates. To illustrate this concept, we discuss a number of very different protein misfolding diseases including phenylketonuria, Parkinson's disease, alpha-1-antitrypsin deficiency, familial neurohypophyseal diabetes insipidus, and short-chain acyl-CoA dehydrogenase deficiency. Despite the differences, an emerging paradigm suggests that the cellular effects of protein misfolding provide a common framework that may contribute to the elucidation of the cell pathology and guide intervention and treatment strategies of many genetic and age-dependent diseases.
Gregersen
Niels
N
Research Unit for Molecular Medicine, Institute of Clinical Medicine, Aarhus University Hospital and Faculty of Health Sciences, University of Aarhus, Skejby Sygehus, 8200 Aarhus N, Denmark. nig@ki.au.dk
Bross
Peter
P
Vang
Søren
S
Christensen
Jane H
JH
D000375:Aging; D004198:Disease Susceptibility / Q000209:etiology*; D030342:Genetic Diseases, Inborn / Q000209:etiology*; D006801:Humans; D019636:Neurodegenerative Diseases / Q000209:etiology; D011489:Protein Denaturation; D017510:Protein Folding