Increased oxidation, glycoxidation, and lipoxidation of brain proteins in prion disease.
The basic molecular underpinnings of the pathological changes that unfold in prion disease remain elusive. A key role of increased oxidative stress has been hypothesized. Given the transient nature of most intermediate molecules implicated, increased oxidative stress is better assessed by quantitating the damage it causes to macromolecules. We used mass spectrometry-based methods to measure specific products of protein oxidation, glycoxidation, and lipoxidation in brains from patients suffering from Creutzfeldt-Jakob disease and Syrian hamsters affected by scrapie. In both cases, increased amounts of glutamic and aminoadipic semialdehydes, products of metal-catalyzed oxidation, malondialdehydelysine (a product of lipoxidation), N-epsilon-carboxyethyllysine (a product of glycoxidation), and N-epsilon-carboxymethyllysine (generated by lipoxidation and glycoxidation) were measured. PrP(Sc), the infectious isoform of the prion protein that accumulates in prion disease, was itself shown to be a target of increased oxidative modification. These changes were accompanied by alterations in fatty acid composition and increased phosphorylation of ERK(1/2) and p38, protein kinases known to respond to increased flows of ROS. These data support an important role of oxidative damage in the pathology of prion disease.
Pamplona
Reinald
R
Metabolic Pathophysiology Research Group, Departament de Medicina Experimental, Universitat de Lleida-IRBLLEIDA, Lleida 25008, Catalonia, Spain.
Naudí
Alba
A
Gavín
Rosalina
R
Pastrana
Miguel A
MA
Sajnani
Gustavo
G
Ilieva
Ekaterina V
EV
Del Río
José Antonio
JA
Portero-Otín
Manuel
M
Ferrer
Isidre
I
Requena
Jesús R
JR
D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D001923:Brain Chemistry; D006224:Cricetinae; D005227:Fatty Acids / Q000032:analysis / Q000378:metabolism; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D015227:Lipid Peroxidation; D008297:Male; D008647:Mesocricetus; D008875:Middle Aged; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000502:physiology*; D017096:Prion Diseases / Q000378:metabolism*
D005227:Fatty Acids