UNASSIGNED: Free radical-mediated oxidative damage to proteins, lipids, and DNA occurs in neurons during acute @entity1545 and in @entity179 . Membrane lipid peroxidation contributes to @entity528 and death, in part by disrupting neuronal ion homeostasis and cellular bioenergetics. Emerging findings suggest that @entity11838 ( @entity13789 ), an @entity4975 produced during lipid peroxidation, impairs the function of various proteins involved in neuronal homeostasis. Here we tested the hypothesis that @entity13789 impairs the cellular system that removes damaged proteins and organelles, the autophagy-lysosome pathway in @entity35 primary cortical neurons. We found that @entity13789 , at a concentration that causes apoptosis over a 48-72  h period, increases protein levels of @entity5615 II and @entity28190 and within 1 and 4  h of exposure, respectively; @entity5615 II and @entity28190 immunoreactive puncta were observed in the cytoplasm of @entity13789 -treated neurons at 6  h. The extent of up-regulation of @entity28190 and @entity5615 II in response to @entity13789 was not affected by co-treatment with the lysosome inhibitor @entity7999 , suggesting that the effects of @entity13789 on autophagy were secondary to lysosome inhibition. Indeed, we found that neurons exposed to @entity13789 exhibit elevated pH levels, and decreased protein substrate hydrolysis and @entity8647 activity. Neurons exposed to @entity13789 also exhibited the accumulation of K63-linked polyubiquitinated proteins, which are substrates targeted for lysosomal degradation. Moreover, we found that the levels of LAMP2a and constitutively active @entity39152 , and numbers of LAMP2a-positive lysosomes, are decreased in neurons exposed to @entity13789 . Our findings demonstrate that the lipid peroxidation product @entity13789 causes early impairment of lysosomes which may contribute to the accumulation of damaged and dysfunctional proteins and organelles and consequent @entity528 . Because @entity73 is increasingly recognized as an early event in the @entity528 that occurs in @entity179 , our findings suggest a role for @entity13789 in such lysosomal dysfunction.

Early involvement of lysosome dysfunction in the XXXX caused by the lipid peroxidation product @entity11838 .

@entity1545 :: ('MESH:D020214', 'Disease') :: ['brain injuries'] @entity5615 :: ('25291(Tax:10116)', 'Gene') :: ['LC3'] @entity73 :: ('MESH:D003072', 'Disease') :: ['impaired lysosome function'] @entity8647 :: ('64529(Tax:10116)', 'Gene') :: ['cathepsin B'] @entity39152 :: ('108348108', 'Gene') :: ['heat-shock protein 70'] @entity28190 :: ('117268(Tax:10116)', 'Gene') :: ['p62'] @entity179 :: ('MESH:D019636', 'Disease') :: ['neurodegenerative disorders'] @entity13789 :: ('CHEBI:58968', 'Chemical') :: ['HNE'] @entity35 :: ('10116', 'Species') :: ['rat'] @entity7999 :: ('MESH:C040929', 'Chemical') :: ['bafilomycin A1'] @entity4975 :: ('D000079', 'Chemical') :: ['aldehyde'] @entity528 :: ('MESH:D009410', 'Disease') :: ['neuronal death', 'neuronal dysfunction'] @entity11838 :: ('MESH:C027576', 'Chemical') :: ['4-hydroxynonenal']
@entity528 :: (MESH:D009410,Disease) :: ['degeneration of cerebral cortical neurons']
