In:
Journal of Neurochemistry, Wiley, Vol. 140, No. 6 ( 2017-03), p. 845-861
Kurzfassung:
Previously, we have reported that pre‐conditioning of primary rat cortical neurons with brain‐derived neurotrophic factor ( BDNF ) may exert neuroprotective effects against 3‐nitropropionic acid (3‐ NP ), a mitochondrial complex II inhibitor. However, the underlying mechanisms, especially potential involvements of autophagy, remain elusive. In this work, we tested the hypothesis that BDNF may suppress 3‐ NP ‐induced autophagy to exert its neuroprotective effects by inducing the expression of p62/sequestosome‐1 in primary cortical neurons. We found that 3‐ NP increased total level of microtubule‐associated protein 1A/1B‐light chain ( LC )‐3 as well as the LC 3‐ II / LC 3‐I ratio, an index of autophagy, in primary cortical neurons. BDNF decreased LC 3‐ II / LC 3‐I ratio and time‐dependently induced expression of p62. Knockdown of p62 by si RNA restored LC 3‐ II / LC 3‐I ratio and increased total LC 3 levels associated with BDNF exposure; p62 knockdown also abolished BDNF ‐dependent neuroprotection against 3‐ NP . Upstream of p62, we found that BDNF triggered phosphorylation of mammalian target of rapamycin ( mTOR ) and its downstream mediator p70S6K; importantly, the mTOR inhibitor rapamycin reduced both BDNF ‐dependent p62 induction as well as 3‐ NP resistance. BDNF is known to induce c‐Jun in cortical neurons. We found that c‐Jun knockdown in part attenuated BDNF ‐mediated p62 induction, whereas p62 knockdown had no significant effects on c‐Jun expression. In addition to suppressing p62 induction, rapamycin also partially suppressed BDNF ‐induced c‐Jun expression, but c‐Jun knockdown failed to affect mTOR activation. Together, our results suggested that BDNF inhibits 3‐ NP ‐induced autophagy via, at least in part, mTOR /c‐Jun‐dependent induction of p62 expression, together contributing to neuroprotection against mitochondrial inhibition. image
Materialart:
Online-Ressource
ISSN:
0022-3042
,
1471-4159
DOI:
10.1111/jnc.2017.140.issue-6
Sprache:
Englisch
Verlag:
Wiley
Publikationsdatum:
2017
ZDB Id:
2020528-4
SSG:
12
