Transcriptional Upregulation of SCG10 and CAP-23 Is Correlated with Regeneration of the Axons of Peripheral and Central Neurons in Vivo

Mason, Matthew R. J.; Lieberman, A. R.; Grenningloh, Gabriele; Anderson, Patrick N.

doi:10.1006/mcne.2002.1140

Cited by 109 publications

(88 citation statements)

References 59 publications

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“…This SCG10 accumulation in the end bulbs of the proximal stump may be functionally important for axonal regeneration, because SCG10 within growth cones encourages the outgrowth of developing axons (23,(41)(42)(43). Of note, increased levels of SCG10 correlate closely with axon regeneration and sprouting after axon severing and ischemic brain injury (44)(45)(46). Thus, regulation of SCG10 turnover and rapid axonal transport may coordinate distal axonal degeneration and proximal axonal regeneration after injury.…”

Section: Discussionmentioning

confidence: 99%

SCG10 is a JNK target in the axonal degeneration pathway

Shin

Miller

Babetto

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

164

216

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Axons actively self-destruct following genetic, mechanical, metabolic, and toxic insults, but the mechanism of axonal degeneration is poorly understood. The JNK pathway promotes axonal degeneration shortly after axonal injury, hours before irreversible axon fragmentation ensues. Inhibition of JNK activity during this period delays axonal degeneration, but critical JNK substrates that facilitate axon degeneration are unknown. Here we show that superior cervical ganglion 10 (SCG10), an axonal JNK substrate, is lost rapidly from mouse dorsal root ganglion axons following axotomy. SCG10 loss precedes axon fragmentation and occurs selectively in the axon segments distal to transection that are destined to degenerate. Rapid SCG10 loss after injury requires JNK activity. The JNK phosphorylation sites on SCG10 are required for its rapid degradation, suggesting that direct JNK phosphorylation targets SCG10 for degradation. We present a mechanism for the selective loss of SCG10 distal to the injury site. In healthy axons, SCG10 undergoes rapid JNK-dependent degradation and is replenished by fast axonal transport. Injury blocks axonal transport and the delivery of SCG10, leading to the selective loss of the labile SCG10 distal to the injury site. SCG10 loss is functionally important: Knocking down SCG10 accelerates axon fragmentation, whereas experimentally maintaining SCG10 after injury promotes mitochondrial movement and delays axonal degeneration. Taken together, these data support the model that SCG10 is an axonalmaintenance factor whose loss is permissive for execution of the injury-induced axonal degeneration program.A xon loss is a devastating consequence of a wide range of neurological diseases. A hallmark of hereditary neuropathies, glaucoma, and diabetic neuropathy, axon loss also is found early in the progression of debilitating neurodegenerative diseases such as Alzheimer's and Parkinson disease (1, 2). Although the great length of many axons is essential to their function, it also makes them vulnerable to mechanical trauma and to neurotoxins such as chemotherapeutics that interfere with axonal transport (3). Current therapies for axonal degeneration target either the systemic diseases that lead to axon loss or the pain that results from axon dysfunction (4). Therapies targeting the axon breakdown process itself are notably absent. Elucidating the mechanism of axonal degeneration may help to develop such therapies.Axonal degeneration is an actively regulated process that is blocked by the overexpression of the Wallerian degeneration slow (Wld s ) fusion protein or its enzymatically active component NMNAT (5-10). Regulated protein degradation promotes the degeneration of injured axons (11), potentially via the degradation of labile axonal-maintenance factors. Rapid postinjury loss of axonal-maintenance factors is a likely mechanism for promoting axon degeneration. NMNAT2 is the first identified axonal-maintenance factor that is degraded soon after injury. Its loss triggers axonal degeneration, and forced express...

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Section: Discussionmentioning

confidence: 99%

SCG10 is a JNK target in the axonal degeneration pathway

Shin

Miller

Babetto

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

164

216

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“…Injury to the peripheral axons of DRG neurons activates regeneration-associated genes and results in robust axonal outgrowth (65). Successful regeneration is coincident with prolonged expression of genes including CAP-23 and GAP-43 (76). Similarly, the up-regulation of regeneration-associated genes has been observed in corticospinal neurons following a proximal intracortical injury, but not a distal spinal axotomy (77).…”

Section: Importance Of Proteomics In Identifying Mechanismsmentioning

confidence: 99%

Molecular and Cellular Mechanisms of Axonal Regeneration After Spinal Cord Injury

Niekerk

Tuszynski

et al. 2016

Molecular & Cellular Proteomics

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Following axotomy, a complex temporal and spatial coordination of molecular events enables regeneration of the peripheral nerve. In contrast, multiple intrinsic and extrinsic factors contribute to the general failure of axonal regeneration in the central nervous system. In this review, we examine the current understanding of differences in protein expression and post-translational modifications, activation of signaling networks, and environmental cues that may underlie the divergent regenerative capacity of central and peripheral axons. We also highlight key experimental strategies to enhance axonal regeneration via modulation of intraneuronal signaling networks and the extracellular milieu. Finally, we explore potential applications of proteomics to fill gaps in the current understanding of molecular mechanisms underlying regeneration, and to provide insight into the development of more effective approaches to promote axonal regeneration following injury to the nervous system. Molecular & Cellular Proteomics

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“…The failure of a central axonal injury to condition DRG neurons into an actively growing state and induce growth-associated genes (Chong et al, 1994;Smith and Skene, 1997;Mason et al, 2002;Wallquist et al, 2004) suggests that transcription factors induced only after a peripheral axonal injury are the trigger that conditions neurons to regener-ate. ATF3 is highly induced in all injured DRG neurons after peripheral but not central axonal injury and is downregulated on reinnerevation of the peripheral target (Tsujino et al, 2000;Bloechlinger et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

ATF3 Increases the Intrinsic Growth State of DRG Neurons to Enhance Peripheral Nerve Regeneration

Seijffers¹,

Mills²,

Woolf³

2007

J. Neurosci.

361

354

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Peripheral axons of dorsal root ganglion (DRG) neurons, but not their central axons in the dorsal columns, regenerate after injury. However, if the neurons are conditioned by a peripheral nerve injury into an actively growing state, the rate of peripheral axonal growth is accelerated and the injured central axons begin to regenerate. The growth-promoting effects of conditioning injuries have two components, increased axonal growth and a reduced response to inhibitory myelin cues. We have examined which transcription factors activated by peripheral axonal injury may mediate the conditioning effect by regulating expression of effectors that increase the intrinsic growth state of the neurons. Activating transcription factor 3 (ATF3) is a prime candidate because it is induced in all injured DRG neurons after peripheral, but not central, axonal damage. To investigate if ATF3 promotes regeneration, we generated transgenic mice that constitutively express this transcription factor in non-injured adult DRG neurons. The rate of peripheral nerve regeneration was enhanced in the transgenic mice to an extent comparable to that produced by a preconditioning nerve injury. The expression of some growth-associated genes, such as SPRR1A, but not others like GAP-43, was increased in the non-injured neurons. ATF3 increased DRG neurite elongation when cultured on permissive substrates but did not overcome the inhibitory effects of myelin or promote central axonal regeneration in the spinal cord in vivo. We conclude that ATF3 contributes to nerve regeneration by increasing the intrinsic growth state of injured neurons.

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Transcriptional Upregulation of SCG10 and CAP-23 Is Correlated with Regeneration of the Axons of Peripheral and Central Neurons in Vivo

Cited by 109 publications

References 59 publications

SCG10 is a JNK target in the axonal degeneration pathway

SCG10 is a JNK target in the axonal degeneration pathway

Molecular and Cellular Mechanisms of Axonal Regeneration After Spinal Cord Injury

ATF3 Increases the Intrinsic Growth State of DRG Neurons to Enhance Peripheral Nerve Regeneration

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