Proteolytic stress: A unifying concept for the etiopathogenesis of Parkinson's disease

• Published in: Annals of neurology 2003, Vol.53 (S3), p.S73-S86
• Main Authors: McNaught, Kevin St. P., Olanow, C. Warren
• Format: Article
• Language: English
• Subjects: alpha-Synuclein; Cysteine Endopeptidases - genetics; Cysteine Endopeptidases - metabolism; Humans; Lewy Bodies - pathology; Ligases - genetics; Multienzyme Complexes - genetics; Multienzyme Complexes - metabolism; Nerve Degeneration - genetics; Nerve Degeneration - pathology; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Parkinson Disease - genetics; Parkinson Disease - metabolism; Parkinson Disease - pathology; Peptide Hydrolases - genetics; Peptide Hydrolases - metabolism; Point Mutation - genetics; Proteasome Endopeptidase Complex; Substantia Nigra - metabolism; Substantia Nigra - pathology; Synucleins; Thiolester Hydrolases - genetics; Thiolester Hydrolases - metabolism; Ubiquitin Thiolesterase; Ubiquitin-Protein Ligases
• ISSN: 0364-5134; 1531-8249
• DOI: 10.1002/ana.10512

The etiopathogenesis of Parkinson's disease (PD) has been elusive. Recently, several lines of evidence have converged to suggest that defects in the ubiquitin‐proteasome system and proteolytic stress underlie nigral pathology in both familial and sporadic forms of the illness. In support of this concept, mutations in α‐synuclein that cause the protein to misfold and resist proteasomal degradation cause familial PD. Similarly, mutations in two enzymes involved in the normal function of the ubiquitin‐proteasome system, parkin and ubiquitin C‐terminal hydrolase L1, are also associated with hereditary PD. Furthermore, structural and function defects in 26/20S proteasomes with accumulation and aggregation of potentially cytotoxic abnormal proteins have been identified in the substantia nigra pars compacta of patients with sporadic PD. Thus, a defect in protein handling appears to be a common factor in sporadic and the various familial forms of PD. This hypothesis may also account for the vulnerability of the substantia nigra pars compacta in PD, why the disorder is age related, and the nature of the Lewy body. It has also facilitated the development of experimental models that recapitulate the behavioral and pathological features of PD, and hopefully will lead to the development of novel neuroprotective therapies for the disorder. Ann Neurol 2003;53 (suppl 3):S73–S86