Proteasomal inhibition causes loss of nigral tyrosine hydroxylase neurons

• Published in: Annals of neurology Vol. 60; no. 2; pp. 253 - 255
• Main Authors: Schapira, Anthony H. V., Cleeter, Michael W. J., Muddle, John R., Workman, Jane M., Cooper, J. Mark, King, Rosalind H. M.
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.08.2006; Willey-Liss
• Subjects: Animals; Behavior, Animal - drug effects; Biological and medical sciences; Brain Chemistry - drug effects; Chymotrypsin - metabolism; Cysteine Proteinase Inhibitors - pharmacology; Development. Senescence. Regeneration. Transplantation; Fundamental and applied biological sciences. Psychology; Grooming - drug effects; Hand Strength; Isolated neuron and nerve. Neuroglia; Medical sciences; Motor Activity - drug effects; Muscle Tonus - drug effects; Neurology; Neurons - enzymology; Oligopeptides - pharmacology; Postural Balance - drug effects; Proteasome Endopeptidase Complex - drug effects; Rats; Rats, Sprague-Dawley; Reflex - drug effects; Substantia Nigra - cytology; Substantia Nigra - enzymology; Tyrosine 3-Monooxygenase - metabolism; Vertebrates: nervous system and sense organs; Weight Gain - drug effects; Nervous system diseases; Oxidoreductases; Tyrosine 3-monooxygenase; Enzyme; Cell death
• ISSN: 0364-5134; 1531-8249
• DOI: 10.1002/ana.20934

Dysfunction of the ubiquitin‐proteasomal system (UPS) has been implicated in the pathogenesis of Parkinson's disease. The systemic administration of UPS inhibitors has been reported to induce nigrostriatal cell death and model Parkinson's disease pathology in rodents. We administered a synthetic, specific UPS inhibitor (PSI) subcutaneously to rats and quantified substantia nigral tyrosine hydroxylase–positive dopaminergic neurons by stereology. PSI caused a 15% decrease in UPS activity at 2 weeks and a 42% reduction in substantia nigra pars compacta tyrosine hydroxylase–positive neurons at 8 weeks. Systemic inhibition of the UPS warrants further evaluation as a means to model Parkinson's disease. Ann Neurol 2006;60:253–255