The role of chaperones in parkinson's disease and prion diseases

Abstract

The etiologies of neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, polyglutamine diseases, or prion diseases may be diverse; however, aberrations in protein folding, processing, and/or degradation are common features of these entities, implying a role of quality control systems, such as molecular chaperones and the ubiquitinproteasome pathway. There is substantial evidence for a causal role of protein misfolding in the pathogenic process coming from neuropathology, genetics, animal modeling, and biophysics. The presence of protein aggregates in all neurodegenerative diseases gave rise to the hypothesis that protein aggregates, be it intracellular or extracellular deposits, may perturb the cellular homeostasis and disintegrate neuronal function (Table 1). More recently, however, an increasing number of studies have indicated that protein aggregates are not toxic per se and might even serve a protective role by sequestering misfolded proteins. Specifically, experiental models of polyglutamine diseases, Alzheimer's disease, and Parkinson's disease revealed that the appearance of aggregates can be dissociated from neuronal toxicity, while misfolded monomers or oligomeric intermediates seem to be the toxic species. The unique features of molecular chaperones to assist in the folding of nascent proteins and to prevent stress-induced misfolding was the rationale to exploit their effects in different models of neurodegenerative diseases. This chapter concentrates on two neurodegenerative diseases, Parkinson's disease and prion diseases, with a special focus on protein misfolding and a possible role of molecular chaperones. © 2006 Springer-Verlag Berlin Heidelberg.