The p75 Neurotrophin Receptor Can Induce Autophagy and Death of Cerebellar Purkinje Neurons

Florez-McClure, Maria L.; Linseman, Daniel A.; Chu, Charleen T.; Barker, Phil; Bouchard, Ron J.; Le, Shoshona S.; Laessig, Tracey A.; Heidenreich, Kim A.

doi:10.1523/jneurosci.5744-03.2004

Cited by 93 publications

(64 citation statements)

References 87 publications

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“…Therefore, autophagy is critical for the survival of cells during energy depletion (4,26). In contrast to its prosurvival roles, autophagy also mediates cell death (28,36). Autophagic cell death does not seem to require caspases and is sometimes negatively regulated by the activities of caspase 8 (28).…”

Section: Discussionmentioning

confidence: 99%

Autophagy Is Induced in CD4+ T Cells and Important for the Growth Factor-Withdrawal Cell Death

Capan

Zhao

et al. 2006

The Journal of Immunology

253

276

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Autophagy is a tightly regulated catabolic mechanism that degrades proteins and organelles. Autophagy mediates programmed cell death under certain conditions. To determine the role of autophagy in T cells, we examined, in mouse CD4+ T cells, conditions under which autophagy is induced and alterations of the cell fate when autophagy is blocked. We have found that resting naive CD4+ T cells do not contain detectable autophagosomes. Autophagy can be observed in activated CD4+ T cells upon TCR stimulation, cytokine culturing, and prolonged serum starvation. Induction of autophagy in T cells requires JNK and the class III PI3K. Autophagy is inhibited by caspases and mammalian target of rapamycin in T cells. Interestingly, more Th2 cells than Th1 cells undergo autophagy. Th2 cells become more resistant to growth factor-withdrawal cell death when autophagy is blocked using either chemical inhibitors 3-methyladenine, or by RNA interference knockdown of beclin 1 and Atg7. Therefore, autophagy is an important mechanism that controls homeostasis of CD4+ T cells.

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Section: Discussionmentioning

confidence: 99%

Autophagy Is Induced in CD4+ T Cells and Important for the Growth Factor-Withdrawal Cell Death

Capan

Zhao

et al. 2006

The Journal of Immunology

253

276

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“…Impairments in axonal transport could also impact on the autophagy system because peripheral signals are integral to the regulation of this mechanism (Florez-McClure et al, 2004). Moreover, axonal injuries that interrupt trophic signaling and deprive the cell of growth factors have been shown to induce autophagy (Nixon, 2006).…”

Section: Discussionmentioning

confidence: 99%

Motor Neuron Disease Occurring in a Mutant Dynactin Mouse Model Is Characterized by Defects in Vesicular Trafficking

Laird¹,

Farah²,

Ackerley³

et al. 2008

J. Neurosci.

165

137

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Amyotrophic lateral sclerosis (ALS), a fatal and progressive neurodegenerative disorder characterized by weakness, muscle atrophy, and spasticity, is the most common adult-onset motor neuron disease. Although the majority of ALS cases are sporadic, ϳ5-10% are familial, including those linked to mutations in SOD1 (Cu/Zn superoxide dismutase). Missense mutations in a dynactin gene (DCTN1) encoding the p150Glued subunit of dynactin have been linked to both familial and sporadic ALS. To determine the molecular mechanism whereby mutant dynactin p150Glued causes selective degeneration of motor neurons, we generated and characterized mice expressing either wild-type or mutant human dynactin p150 Glued . Neuronal expression of mutant, but not wild type, dynactin p150Glued causes motor neuron disease in these animals that are characterized by defects in vesicular transport in cell bodies of motor neurons, axonal swelling and axo-terminal degeneration. Importantly, we provide evidence that autophagic cell death is implicated in the pathogenesis of mutant p150 Glued mice. This novel mouse model will be instrumental for not only clarifying disease mechanisms in ALS, but also for testing therapeutic strategies to ameliorate this devastating disease.

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“…Uptake efficiency was Ͼ96% in all experiments. Sequences used were as follows: p75 NTR antisense, 5Ј-ACCTGCCCTCCTC-ATTGCA-3Ј, and p75 NTR missense, 5Ј-CTCCCACTCGTCATTC-GAC-3Ј (Florez-McClure et al, 2004). This antisense sequence has previously been shown to be effective at inhibiting p75 NTR -induced apoptosis in motor neurons both in vivo and in vitro (Lowry et al, 2001a;Pehar et al, 2006).…”

Section: Methodsmentioning

confidence: 99%

Mitochondrial Superoxide Production and Nuclear Factor Erythroid 2-Related Factor 2 Activation in p75 Neurotrophin Receptor-Induced Motor Neuron Apoptosis

Pehar

Vargas²,

Robinson³

et al. 2007

J. Neurosci.

114

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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 ( ⅐ NO). 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 ⅐ 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 SOD1 G93A expression, increasing their sensitivity to NGF. In contrast, rising antioxidant defenses by Nrf2 activation prevented NGF-induced apoptosis. Together, our data indicate that p75 NTR -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.

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The p75 Neurotrophin Receptor Can Induce Autophagy and Death of Cerebellar Purkinje Neurons

Cited by 93 publications

References 87 publications

Autophagy Is Induced in CD4+ T Cells and Important for the Growth Factor-Withdrawal Cell Death

Autophagy Is Induced in CD4+ T Cells and Important for the Growth Factor-Withdrawal Cell Death

Motor Neuron Disease Occurring in a Mutant Dynactin Mouse Model Is Characterized by Defects in Vesicular Trafficking

Mitochondrial Superoxide Production and Nuclear Factor Erythroid 2-Related Factor 2 Activation in p75 Neurotrophin Receptor-Induced Motor Neuron Apoptosis

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