DLK-dependent signaling is important for somal but not axonal degeneration of retinal ganglion cells following axonal injury

Fernandes, Kimberly A.; Harder, Jeffrey M; John, Simon W. M.; Shrager, Peter; Libby, Richard T.

doi:10.1016/j.nbd.2014.05.015

Cited by 80 publications

(129 citation statements)

References 48 publications

(113 reference statements)

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“…Thus, different aspects of RGC decline may occur at different rates or be regulated by distinct mechanisms. Consistent with this, deficiency in the dual leucine kinase (Dlk) signaling pathway alters somal but not axonal RGC degeneration (Fernandes et al, 2014). In contrast to our findings, significant reductions in beta tubulin III labeled RGCs were observed in a transient ocular hypertension model of glaucoma in Cx3cr1 gfp/gfp C57Bl6/J mice (Wang et al, 2014).…”

Section: Discussionmentioning

confidence: 85%

“…This is also the case for diverse neurodegenerative ocular diseases, including glaucoma (Karlstetter et al, 2015). In glaucoma, retinal ganglion cells (RGCs) progressively degenerate, with the different neuronal compartments (soma, axon, dendrites, and synapses) declining at different times and potentially by different mechanisms (Libby et al, 2005a; Whitmore et al, 2005; Conforti et al, 2007; Howell et al, 2007; Calkins, 2012; Fernandes et al, 2014). In addition, multiple studies in human and experimental glaucoma suggest a link between the progressive deterioration of RGCs and alterations of glial cell types (Yuan and Neufeld, 2001; Naskar et al, 2002; Neufeld and Liu, 2003; Nakazawa et al, 2006; Inman and Horner, 2007; Bosco et al, 2011, 2015b; Lye-Barthel et al, 2013; Chong and Martin, 2015).…”

Section: Introductionmentioning

confidence: 99%

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Loss of Fractalkine Signaling Exacerbates Axon Transport Dysfunction in a Chronic Model of Glaucoma

et al. 2016

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Neurodegeneration in glaucoma results in decline and loss of retinal ganglion cells (RGCs), and is associated with activation of myeloid cells such as microglia and macrophages. The chemokine fractalkine (FKN or Cx3cl1) mediates communication from neurons to myeloid cells. Signaling through its receptor Cx3cr1 has been implicated in multiple neurodegenerative diseases, but the effects on neuronal pathology are variable. Since it is unknown how FKN-mediated crosstalk influences RGC degeneration in glaucoma, we assessed this in a chronic mouse model, DBA/2J. We analyzed a DBA/2J substrain deficient in Cx3cr1, and compared compartmentalized RGC degeneration and myeloid cell responses to those in standard DBA/2J mice. We found that loss of FKN signaling exacerbates axon transport dysfunction, an early event in neurodegeneration, with a significant increase in RGCs with somal accumulation of the axonal protein phosphorylated neurofilament, and reduced retinal expression of genes involved in axon transport, Kif1b, and Atp8a2. There was no change in the loss of Brn3-positive RGCs, and no difference in the extent of damage to the proximal optic nerve, suggesting that the loss of fractalkine signaling primarily affects axon transport. Since Cx3cr1 is specifically expressed in myeloid cells, we assessed changes in retinal microglial number and activation, changes in gene expression, and the extent of macrophage infiltration. We found that loss of fractalkine signaling led to innate immune changes within the retina, including increased infiltration of peripheral macrophages and upregulated nitric oxide synthase-2 (Nos-2) expression in myeloid cells, which contributes to the production of NO and can promote axon transport deficits. In contrast, resident retinal microglia appeared unchanged either in number, morphology, or expression of the myeloid activation marker ionized calcium binding adaptor molecule 1 (Iba1). There was also no significant increase in the proinflammatory gene interleukin 1 beta (Il1β). We conclude that loss of fractalkine signaling causes a selective worsening of axon transport dysfunction in RGCs, which is linked to enhanced Nos-2 expression in myeloid cells. Our findings suggest that distinct mechanisms may contribute to different aspects of RGC decline in glaucoma, with axonal transport selectively altered after loss of Cx3cr1 in microglia and/or macrophages.

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Section: Discussionmentioning

confidence: 85%

Section: Introductionmentioning

confidence: 99%

Loss of Fractalkine Signaling Exacerbates Axon Transport Dysfunction in a Chronic Model of Glaucoma

et al. 2016

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“…Deletion of DLK expression in an optic nerve crush model provided significant RGC survival (Welsbie et al, 2013), and reduced expression of stress response, inflammatory and apoptotic genes, like ATF3, CHOP and Bim , but had little effect on regenerative properties of the axon after injury (Watkins et al, 2013). It was recently shown that Dlk -deficiency delayed somal RGC death after optic nerve injury, but axonal degeneration was unaffected (Fernandes et al, 2014). Downstream targets for DLK include MKK4/7 and JNK activation, the latter of which can participate in a feedback loop and stabilize DLK activity (Huntwork-Rodriguez et al, 2013).…”

Section: The Role Of Bax In Mouse Retinal Ganglion Cell Pathophysimentioning

confidence: 99%

BAX to basics: How the BCL2 gene family controls the death of retinal ganglion cells

Maes

Schlamp

Nickells

2017

Progress in Retinal and Eye Research

161

120

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Retinal ganglion cell (RGC) death is the principal consequence of injury to the optic nerve. For several decades, we have understood that the RGC death process was executed by apoptosis, suggesting that there may be ways to therapeutically intervene in this cell death program and provide a more direct treatment to the cells and tissues affected in diseases like glaucoma. A major part of this endeavor has been to elucidate the molecular biological pathways active in RGCs from the point of axonal injury to the point of irreversible cell death. A major component of this process is the complex interaction of members of the BCL2 gene family. Three distinct family members of proteins orchestrate the most critical junction in the apoptotic program of RGCs, culminating in the activation of pro-apoptotic BAX. Once active, BAX causes irreparable damage to mitochondria, while precipitating downstream events that finish off a dying ganglion cell. This review is divided into two major parts. First, we summarize the extent of knowledge of how BCL2 gene family proteins interact to facilitate the activation and function of BAX. This area of investigation has rapidly changed over the last few years and has yielded a dramatically different mechanistic understanding of how the intrinsic apoptotic program is run in mammalian cells. Second, we provided a comprehensive analysis of nearly two decades of investigation of the role of BAX in the process of RGC death, much of which has provided many important insights into the overall pathophysiology of diseases like glaucoma.

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“…There is some disagreement regarding the role of DLK1 in RGCs. Axon degeneration was not delayed after optic nerve crush in DLK1-deficient mice (Fernandes et al, 2014). While this suggests that kinases other than DLK1 may be capable of JNK activation for axon degeneration, a separate study showed that phosphorylation of c-Jun, a target of JNK, was dependent on DLK1 after optic nerve crush (Watkins et al, 2013).…”

Section: Energy In Axonsmentioning

confidence: 99%

“…DLK-1, after trophic deprivation, is JNK dependent and contributes to both axon degeneration and cell body apoptosis (Ghosh et al, 2011). Interestingly, DLK1 knockout in a optic nerve crush model did not protect RGC axon structure or function as measured by CAP amplitude (Fernandes et al, 2014), suggesting that degeneration in these axons is governed differently than those in development (Hoopfer et al, 2006) and potentially other sensory systems (Miller et al, 2009). Others determined that deficiency in DLK1 protected RGC somas from apoptosis and proximal axons from degeneration after optic nerve crush (Watkins et al, 2013).…”

Section: Energy In Axonsmentioning

confidence: 99%

Metabolic Vulnerability in the Neurodegenerative Disease Glaucoma

Inman

Harun‐Or‐Rashid

2017

Front. Neurosci.

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Axons can be several orders of magnitude longer than neural somas, presenting logistical difficulties in cargo trafficking and structural maintenance. Keeping the axon compartment well supplied with energy also presents a considerable challenge; even seemingly subtle modifications of metabolism can result in functional deficits and degeneration. Axons require a great deal of energy, up to 70% of all energy used by a neuron, just to maintain the resting membrane potential. Axonal energy, in the form of ATP, is generated primarily through oxidative phosphorylation in the mitochondria. In addition, glial cells contribute metabolic intermediates to axons at moments of high activity or according to need. Recent evidence suggests energy disruption is an early contributor to pathology in a wide variety of neurodegenerative disorders characterized by axonopathy. However, the degree to which the energy disruption is intrinsic to the axon vs. associated glia is not clear. This paper will review the role of energy availability and utilization in axon degeneration in glaucoma, a chronic axonopathy of the retinal projection.

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DLK-dependent signaling is important for somal but not axonal degeneration of retinal ganglion cells following axonal injury

Cited by 80 publications

References 48 publications

Loss of Fractalkine Signaling Exacerbates Axon Transport Dysfunction in a Chronic Model of Glaucoma

Loss of Fractalkine Signaling Exacerbates Axon Transport Dysfunction in a Chronic Model of Glaucoma

BAX to basics: How the BCL2 gene family controls the death of retinal ganglion cells

Metabolic Vulnerability in the Neurodegenerative Disease Glaucoma

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