20S proteasome mediated degradation of DHFR: implications in neurodegenerative disorders

• Published in: Archives of biochemistry and biophysics Vol. 422; no. 2; pp. 168 - 174
• Main Authors: Amici, Manila, Sagratini, Danila, Pettinari, Assuntina, Pucciarelli, Stefania, Angeletti, Mauro, Eleuteri, Anna Maria
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 15-02-2004
• Subjects: 20S proteasome; Animals; Cattle; Cysteine Endopeptidases - metabolism; Dihydrofolate reductase; Hydrolysis; Liver - enzymology; Methotrexate - pharmacology; Multienzyme Complexes - metabolism; Neurodegenerative Diseases - enzymology; Neurodegenerative Diseases - pathology; Neurodegenerative pathologies; Oxidation; Oxidation-Reduction; Peroxynitrous Acid - pharmacology; Proteasome Endopeptidase Complex; Spectrometry, Fluorescence; Tetrahydrofolate Dehydrogenase - metabolism; Neurodegenerative pathologies; 20S proteasome; Oxidation; Dihydrofolate reductase
• ISSN: 0003-9861; 1096-0384
• DOI: 10.1016/j.abb.2003.12.014

The 20S proteasome is responsible for the degradation of protein substrates implicated in the onset and progression of neurodegenerative disorders, such as α-synuclein and tau protein. Here we show that the 20S proteasome isolated from bovine brain directly hydrolyzes, in vitro, the dihydrofolate reductase (DHFR), demonstrated to be involved in the pathogenesis of neurodegenerative diseases. Furthermore, the DHFR susceptibility to proteolysis is enhanced by oxidative conditions induced by peroxynitrite, mimicking the oxidative environment typical of these disorders. The results obtained suggest that the folate metabolism may be impaired by an increased degradation of DHFR, mediated by the 20S proteasome.