JNK regulates FoxO-dependent autophagy in neurons

Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.
Genes & development (Impact Factor: 10.8). 02/2011; 25(4):310-22. DOI: 10.1101/gad.1984311
Source: PubMed


The cJun N-terminal kinase (JNK) signal transduction pathway is implicated in the regulation of neuronal function. JNK is encoded by three genes that play partially redundant roles. Here we report the creation of mice with targeted ablation of all three Jnk genes in neurons. Compound JNK-deficient neurons are dependent on autophagy for survival. This autophagic response is caused by FoxO-induced expression of Bnip3 that displaces the autophagic effector Beclin-1 from inactive Bcl-XL complexes. These data identify JNK as a potent negative regulator of FoxO-dependent autophagy in neurons.

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    • "Aside from irregularities in M1, these behaviors could in principle result from progressive decline in muscle tone, or from degeneration of cerebellar input. There is a pretext for a cerebellar component, as targeted deletion of Jnks 1, 2, and 3 (Xu et al., 2011) or knockout of Jnk1 (Björkblom et al., 2005; Xu et al., 2011), alters Purkinje neuron dendrite architecture. Moreover, altered stride width, a classic hallmark of cerebellar dysfunction (Gilman et al., 1981), is reduced in young adult mice lacking Jnk1-/-. "
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    ABSTRACT: Genetic anomalies on the JNK pathway confer susceptibility to autism spectrum disorders, schizophrenia, and intellectual disability. The mechanism whereby a gain or loss of function in JNK signaling predisposes to these prevalent dendrite disorders, with associated motor dysfunction, remains unclear. Here we find that JNK1 regulates the dendritic field of L2/3 and L5 pyramidal neurons of the mouse motor cortex (M1), the main excitatory pathway controlling voluntary movement. In Jnk1-/- mice, basal dendrite branching of L5 pyramidal neurons is increased in M1, as is cell soma size, whereas in L2/3, dendritic arborization is decreased. We show that JNK1 phosphorylates rat HMW-MAP2 on T1619, T1622, and T1625 (Uniprot P15146) corresponding to mouse T1617, T1620, T1623, to create a binding motif, that is critical for MAP2 interaction with and stabilization of microtubules, and dendrite growth control. Targeted expression in M1 of GFP-HMW-MAP2 that is pseudo-phosphorylated on T1619, T1622, and T1625 increases dendrite complexity in L2/3 indicating that JNK1 phosphorylation of HMW-MAP2 regulates the dendritic field. Consistent with the morphological changes observed in L2/3 and L5, Jnk1-/- mice exhibit deficits in limb placement and motor coordination, while stride length is reduced in older animals. In summary, JNK1 phosphorylates HMW-MAP2 to increase its stabilization of microtubules while at the same time controlling dendritic fields in the main excitatory pathway of M1. Moreover, JNK1 contributes to normal functioning of fine motor coordination. We report for the first time, a quantitative Sholl analysis of dendrite architecture, and of motor behavior in Jnk1-/- mice. Our results illustrate the molecular and behavioral consequences of interrupted JNK1 signaling and provide new ground for mechanistic understanding of those prevalent neuropyschiatric disorders where genetic disruption of the JNK pathway is central.
    Frontiers in Cellular Neuroscience 09/2014; 8:272. DOI:10.3389/fncel.2014.00272 · 4.29 Impact Factor
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    • "It stimulates dendrite formation, axodendritic length, axonal regeneration, mediates fast axonal transport, and contributes to the regulation of synaptic plasticity (Bjorkblom et al., 2005; Chen et al., 2005; Zhu et al., 2005; Tararuk et al., 2006; Thomas et al., 2008a; Morfini et al., 2009; Barnat et al., 2010; Podkowa et al., 2010). At the same time it has been linked to stress-induced apoptosis in different pathological conditions as a result of its inhibition of autophagy and the induction of pro-apoptotic BCL-2 family members (Jia et al., 2006; Hubner et al., 2008; Xu et al., 2011). In our cell culture system, miR-7 and miR-153 overexpression significantly lifted SAPK/JNK activation in the MPP+-treated neurons. "
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    ABSTRACT: Differential expression of microRNAs (miRs) in the brain of patients with neurodegenerative diseases suggests that they may have key regulatory roles in the development of these disorders. Two such miRs, miR-7, and miR-153 have recently been shown to target α-synuclein, a protein critically involved in the pathological process of Parkinson's disease. By using a well-established in culture Parkinson's disease model that of neurotoxin 1-Methyl-4-Phenyl-Pyridinium (MPP(+)), we examined whether miR-7 and miR-153 display neuroprotective properties. Herein, we demonstrate that treatment of cortical neurons with MPP(+) induced a dose-dependent cell death with apoptotic characteristics. This was reflected in altered intracellular signaling characterized by increased levels of activated kinases p38MAPK and ERK1/2 and reduced levels of activated AKT, p70S6K, and SAPK/JNK. Overexpression of miR-7 or miR-153 by adenoviral transduction protected cortical neurons from MPP(+)-induced toxicity, restored neuronal viability and anti-apoptotic BCL-2 protein levels while attenuated activation of caspase-3. Moreover, both miR-7 and miR-153 interfered with MPP(+)-induced alterations in intracellular signaling pathways in a partially overlapping manner; specifically, they preserved activation of mTOR and SAPK/JNK signaling pathways in the MPP(+)-treated neurons, while miR-153 also attenuated MPP(+)-induced activation of p38MAPK. No major effects were observed in the rest of signaling cascades or proteins investigated. Furthermore, the neuroprotective effect of miR-7 and miR-153 was alleviated when MPP(+) was co-administered with rapamycin. Taken together, our results suggest that miR-7 and miR-153 protect neurons from cell death by interfering with the MPP(+)-induced downregulation of mTOR signaling.
    Frontiers in Cellular Neuroscience 07/2014; 8:182. DOI:10.3389/fncel.2014.00182 · 4.29 Impact Factor
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    • "JNK can act as a negative regulator of FoxO-dependent autophagy in neurons (Xu et al., 2011). It is interesting to note that, although Atg9 overexpression activates JNK, our data showed that Atg9 overexpression could not induce autophagy in the larval fat body. "
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    ABSTRACT: Autophagy is a highly conserved catabolic process that degrades and recycles intracellular components through the lysosomes. Atg9 is the only integral membrane protein among autophagy-related (Atg) proteins thought to carry the membrane source for forming autophagosomes. Here we show that Drosophila Atg9 interacts with Drosophila tumor necrosis factor receptor-associated factor 2 (dTRAF2) to regulate the c-Jun N-terminal kinase (JNK) signaling pathway. Significantly, depletion of Atg9 and dTRAF2 compromised JNK-mediated intestinal stem cell proliferation and autophagy induction upon bacterial infection and oxidative stress stimulation. In mammalian cells, mAtg9 interacts with TRAF6, the homolog of dTRAF2, and plays an essential role in regulating oxidative stress-induced JNK activation. Moreover, we found that ROS-induced autophagy acts as a negative feedback regulator of JNK activity by dissociating Atg9/mAtg9 from dTRAF2/TRAF6 in Drosophila and mammalian cells, respectively. Our findings indicate a dual role for Atg9 in the regulation of JNK signaling and autophagy under oxidative stress conditions.
    Developmental Cell 11/2013; 27(5). DOI:10.1016/j.devcel.2013.10.017 · 9.71 Impact Factor
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