4.7 Article

Mitochondrial superoxide production and nuclear factor erythroid 2-related factor 2 activation in p75 neurotrophin receptor-induced motor neuron apoptosis

Journal

JOURNAL OF NEUROSCIENCE
Volume 27, Issue 29, Pages 7777-7785

Publisher

SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.0823-07.2007

Keywords

amyotrophic lateral sclerosis; mitochondria; motor neurons; nerve growth factor; Nrf2; p75(NTR); superoxide

Categories

Funding

  1. FIC NIH HHS [R03TW006482, R03 TW006482] Funding Source: Medline
  2. NCCIH NIH HHS [AT02034, P01 AT002034] Funding Source: Medline
  3. NIEHS NIH HHS [ES00210, P30 ES000210, P01 ES000040, ES00040] Funding Source: Medline

Ask authors/readers for more resources

Nerve growth factor (NGF) can induce apoptosis by signaling through the p75 neurotrophin receptor (p75(NTR)) in several nerve cell populations. Cultured embryonic motor neurons expressing p75(NTR) are not vulnerable to NGF unless they are exposed to an exogenous flux of nitric oxide ((NO)-N-.). In the present study, we show that p75(NTR)-mediated apoptosis in motor neurons involved neutral sphingomyelinase activation, increased mitochondrial superoxide production, and cytochrome c release to the cytosol. The mitochondria-targeted antioxidants mitoQ and mitoCP prevented neuronal loss, further evidencing the role of mitochondria in NGF-induced apoptosis. In motor neurons overexpressing the amyotrophic lateral sclerosis (ALS)-linked superoxide dismutase 1(G93A) (SOD1(G93A)) mutation, NGF induced apoptosis even in the absence of an external source of (.) NO. The increased susceptibility of SOD1(G93A) motor neurons to NGF was associated to decreased nuclear factor erythroid 2-related factor 2 (Nrf2) expression and downregulation of the enzymes involved in glutathione biosynthesis. In agreement, depletion of glutathione in nontransgenic motor neurons reproduced the effect of SOD1G93A expression, increasing their sensitivity to NGF. In contrast, rising antioxidant defenses by Nrf2 activation prevented NGF- induced apoptosis. Together, our data indicate that p75NTR- mediated motor neuron apoptosis involves ceramide- dependent increased mitochondrial superoxide production. This apoptotic pathway is facilitated by the expression of ALS- linked SOD1 mutations and critically modulated by Nrf2 activity.

Authors

I am an author on this paper
Click your name to claim this paper and add it to your profile.

Reviews

Primary Rating

4.7
Not enough ratings

Secondary Ratings

Novelty
-
Significance
-
Scientific rigor
-
Rate this paper

Recommended

No Data Available
No Data Available