N-alpha-p-tosyl-l-lysine chloromethyl ketone (TLCK) suppresses neuritic degeneration caused by different experimental paradigms including in vitro Wallerian degeneration

Ikegami, Koji; Kato, Satoko; Koike, Takao

doi:10.1016/j.brainres.2004.09.050

Cited by 22 publications

(15 citation statements)

References 41 publications

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“…Thus, a successful strategy for slowing or preventing axon degeneration has been to indirectly provide energy (Araki et al, 2004; Chung et al, 2013). Wallerian degeneration, the most likely mechanism by which glaucomatous RGC axons die, can be halted through increased NAD+ biosynthesis (Araki et al, 2004) and the action of a serine protease inhibitor that prevents ATP decrease (Ikegami et al, 2004). Despite NAD+ being an obvious candidate effector for axon protection, overexpression of Wld s and NMNAT prevents axon degeneration but does not increase basal NAD+ levels (Mack et al, 2001; Araki et al, 2004), and NAD+ levels are not essential to axon preservation (Sasaki et al, 2009).…”

Section: Addressing Energy Failure In Glaucomamentioning

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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Section: Addressing Energy Failure In Glaucomamentioning

confidence: 99%

Metabolic Vulnerability in the Neurodegenerative Disease Glaucoma

Inman

Harun‐Or‐Rashid

2017

Front. Neurosci.

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“…This indicates that neurite degeneration caused by NGF deprivation and Zn 2+ chelators shares the same mechanism caused by energy impairment characterized by nonapoptosis. However, there are some differences as well: for example, neuritc degeneration after NGF deprivation occurred slowly (48 hr; Ikegami et al, 2004) compared with that caused by intracellular zinc chelation here (24 hr). Notably, neurite degeneration induced by zinc chelators is morphologically different from NGF withdrawal in that the severe retraction and detachment caused by NGF deprivation were not observed in neurites exposed to the zinc chelator.…”

Section: Discussionmentioning

confidence: 91%

“…Photomicrographs were taken by an Olympus phase‐contrast microscope IX70 (Olympus Optical, Tokyo) equipped with Nikon digital camera (Coolpix, Nikon Optical, Tokyo), then stored and processed on a personal computer. Beadings are defined as any spherical protrusions from neurites that appear only during neurite degeneration, but not under control conditions, in the presence of NGF (Ikegami et al, 2004). Neurites were randomly picked up, and the number of beadings per 100‐μm length was counted.…”

Section: Methodsmentioning

confidence: 99%

Cellular Zn²⁺ chelators cause “dying‐back” neurite degeneration associated with energy impairment

Yang

Kawataki

Fukui

et al. 2007

J of Neuroscience Research

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Most cellular zinc is tightly associated with metalloproteins and other Zn2+-dependent proteins, which along with cellular Zn2+ compartments may coordinately regulate cytoplasmic free Zn2+ levels in the picomolar range. Moreover, Zn2+-containing endosomes or protein complexes appear to move along axons or dendrites, suggesting a dynamic mechanism for trafficking, exchanging, or scavenging Zn2+ and/or Zn2+ protein complexes in neurons. It is therefore interesting to examine whether cellular Zn2+ levels might alter neurite integrity and dynamics. Here we show that membrane-permeable zinc chelators, including 1,10-phenanthroline, N,N,N',N'-tetrakis-(2-pyridylmethyl)-ethylenediamine (TPEN), and zinquin, selectively elicit axon and dendrite degeneration but leave the cell body intact in sympathetic neurons. The process begins distally and then moves retrogradely, with a distinct "dying-back" pattern. An inactive isomer of 1,10-phenanthroline failed to cause neuite degeneration, and these chelators mediated their effects by selectively chelating Zn2+, but not other metals. Moreover, neurite degeneration was associated with a decrease in neuritic ATP levels and was caused by energy failure, because an exogenous supply of nicotinamide adenine dinucleotide (NAD) or its precursor nicotinamide suppressed the degeneration by delaying axonal ATP reduction caused by Zn2+ depletion. Blockage of autophagy by 3-methyladenine provided partial protection against degeneration of terminal axons or dendrites; there was, however, no obvious alteration in that of medial portions. Collectively, our results show that cellular Zn2+ depletion induces a "dying-back" degeneration characterized by an NAD- and autophagy-dependent process, independently of neurite elongation dynamics.

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“…Interestingly, U0126 has previously been shown to reduce ATP levels in cultured cells resulting in an increased AMP:ATP ratio and activation of AMPK via what appears to be a MEK-independent mechanism [31]–[33]. Since declining ATP levels might contribute to the initiation or execution of Wallerian degeneration [34], a U0126-mediated reduction in ATP could thus account for its effects on preservation of transected axons, although PD184352 may have similar off-target effects in some cell types [31]. Interestingly, mitochondrial ATP production and Ca 2+ buffering have respectively been shown to be enhanced in Wld S mice and in transgenic flies expressing Wld S [35], [36].…”

Section: Discussionmentioning

confidence: 99%

MEK Inhibitor U0126 Reverses Protection of Axons from Wallerian Degeneration Independently of MEK–ERK Signaling

et al. 2013

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Wallerian degeneration is delayed when sufficient levels of proteins with NMNAT activity are maintained within axons after injury. This has been proposed to form the basis of 'slow Wallerian degeneration' (Wld S), a neuroprotective phenotype conferred by an aberrant fusion protein, WldS. Proteasome inhibition also delays Wallerian degeneration, although much less robustly, with stabilization of NMNAT2 likely to play a key role in this mechanism. The pan-MEK inhibitor U0126 has previously been shown to reverse the axon-protective effects of proteasome inhibition, suggesting that MEK-ERK signaling plays a role in delayed Wallerian degeneration, in addition to its established role in promoting neuronal survival. Here we show that whilst U0126 can also reverse WldS-mediated axon protection, more specific inhibitors of MEK1/2 and MEK5, PD184352 and BIX02189, have no significant effect on the delay to Wallerian degeneration in either situation, whether used alone or in combination. This suggests that an off-target effect of U0126 is responsible for reversion of the axon protective effects of WldS expression or proteasome inhibition, rather than inhibition of MEK1/2-ERK1/2 or MEK5-ERK5 signaling. Importantly, this off-target effect does not appear to result in alterations in the stabilities of either WldS or NMNAT2.

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N-alpha-p-tosyl-l-lysine chloromethyl ketone (TLCK) suppresses neuritic degeneration caused by different experimental paradigms including in vitro Wallerian degeneration

Cited by 22 publications

References 41 publications

Metabolic Vulnerability in the Neurodegenerative Disease Glaucoma

Metabolic Vulnerability in the Neurodegenerative Disease Glaucoma

Cellular Zn²⁺ chelators cause “dying‐back” neurite degeneration associated with energy impairment

MEK Inhibitor U0126 Reverses Protection of Axons from Wallerian Degeneration Independently of MEK–ERK Signaling

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N-alpha-p-tosyl-l-lysine chloromethyl ketone (TLCK) suppresses neuritic degeneration caused by different experimental paradigms including in vitro Wallerian degeneration

Cited by 22 publications

References 41 publications

Metabolic Vulnerability in the Neurodegenerative Disease Glaucoma

Metabolic Vulnerability in the Neurodegenerative Disease Glaucoma

Cellular Zn2+ chelators cause “dying‐back” neurite degeneration associated with energy impairment

MEK Inhibitor U0126 Reverses Protection of Axons from Wallerian Degeneration Independently of MEK–ERK Signaling

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Cellular Zn²⁺ chelators cause “dying‐back” neurite degeneration associated with energy impairment