Protein misfolding and cellular defense mechanisms in neurodegenerative diseases

Introduction In many major neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), Alzheimer's disease, Parkinson's disease, and several hereditary diseases caused by expansions of polyglutamine (PolyQ) tracts (e.g. Huntington's disease and the spinocerebellar ataxias) (Table 9.1), the pathology and the eventual death of specific neuronal populations occur due to the accumulation of specific abnormal polypeptides, which form insoluble intracellular inclusions. Many observations suggest that these various types of inclusions arise through common mechanisms and elicit similar host responses. For example, all these inclusions contain components of the ubiquitin-proteasome degradation pathway and also molecular chaperones, which represent the two main systems that eukaryotic cells use to protect themselves against the buildup of unfolded polypeptides. The accumulation of abnormal polypeptides in the form of inclusions in various neurological disorders must result from an inability of neurons to either refold or degrade these abnormal species. Because these neurological diseases are of late onset, and the very same mutant proteins are expressed without causing obvious pathology in younger individuals, it seems likely that the failure to adequately deal with these abnormal molecules progresses with aging. Because the continued accumulation of unfolded, non-functional polypeptides is likely to cause cell toxicity, it is not surprising that defense mechanisms emerged early in evolution that enable cells to withstand the appearance of large amounts of unfolded proteins, as may result from mutations, errors in protein synthesis, or inefficient folding of nascent polypeptides.