20S proteasome mediated degradation of DHFR: implications in neurodegenerative disorders.
The 20S proteasome is responsible for the degradation of protein substrates implicated in the onset and progression of neurodegenerative disorders, such as alpha-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.
Amici
Manila
M
Department of Molecular, Cellular and Animal Biology, Post-Graduate School in Clinical Biochemistry, University of Camerino, 62032 Camerino (MC), Italy.
Sagratini
Danila
D
Pettinari
Assuntina
A
Pucciarelli
Stefania
S
Angeletti
Mauro
M
Eleuteri
Anna Maria
AM
D000818:Animals; D002417:Cattle; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D006868:Hydrolysis; D008099:Liver / Q000201:enzymology; D008727:Methotrexate / Q000494:pharmacology; D009097:Multienzyme Complexes / Q000378:metabolism*; D019636:Neurodegenerative Diseases / Q000201:enzymology* / Q000473:pathology; D010084:Oxidation-Reduction; D030421:Peroxynitrous Acid / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex; D013050:Spectrometry, Fluorescence; D013762:Tetrahydrofolate Dehydrogenase / Q000378:metabolism*
D009097:Multienzyme Complexes; D030421:Peroxynitrous Acid; D013762:Tetrahydrofolate Dehydrogenase; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D008727:Methotrexate