Microtubule‐dependent processes precede pathological calcium influx in excitotoxin‐induced axon degeneration

Tian, Nan; Hanson, Kelsey; Canty, AJ; Vickers, James C.; King, Anna E.

doi:10.1111/jnc.14909

Cited by 10 publications

(6 citation statements)

References 58 publications

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“…43 Although this might very well be associated with structural changes that occur in many cells in response to MA, it may also be related to cellular toxicity. Stabilization of microtubules can reduce axonal degeneration via increases in tubulin acetylation 44 and inhibition of Vdac-tubulin interactions may promote cell death. 45 The molecular target generally considered to be responsible for the psychostimulant and addictive effects of MA, the dopamine transporter (DAT), was not identified.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

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Combining Neurobehavioral Analysis and In Vivo Photoaffinity Labeling to Understand Protein Targets of Methamphetamine in Casper Zebrafish

Tackie‐Yarboi

Wisner

Horton

et al. 2020

ACS Chem. Neurosci.

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Photoaffinity labeling (PAL) remains one of the most widely utilized methods of determining protein targets of drugs. Although useful, the scope of this technique has been limited to in vitro applications because of the inability of UV light to penetrate whole organisms. Herein, pigment-free Casper zebrafish were employed to allow in vivo PAL. A methamphetamine-related phenethylamine PAL probe, designated here as 2, demonstrated dose-dependent effects on behavior similar to methamphetamine and permitted concentration-dependent labeling of protein binding partners. Click chemistry was used to analyze binding partners via fluoroimaging. Conjugation to a biotin permitted streptavidin pull-down and proteomic analysis to define direct binding partners of the methamphetamine probe. Bioinformatic analysis revealed the probe was chiefly bound to proteins involved in phagocytosis and mitochondrial function. Future applications of this experimental paradigm combining examination of drug–protein binding interactions alongside neurobehavioral readouts via in vivo PAL will significantly enhance our understanding of drug targets, mechanism(s) of action, and toxicity/lethality.

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Section: ■ Results and Discussionmentioning

confidence: 99%

“…Although this might very well be associated with structural changes that occur in many cells in response to MA, it may also be related to cellular toxicity. Stabilization of microtubules can reduce axonal degeneration via increases in tubulin acetylation and inhibition of Vdac-tubulin interactions may promote cell death …”

Section: Resultsmentioning

confidence: 99%

Combining Neurobehavioral Analysis and In Vivo Photoaffinity Labeling to Understand Protein Targets of Methamphetamine in Casper Zebrafish

Tackie‐Yarboi

Wisner

Horton

et al. 2020

ACS Chem. Neurosci.

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show abstract

“…While the pathways downstream of spheroid formation require further investigation, it is intriguing to speculate that the rupture of these spheroids and release of their contents may recruit macrophages and/or modulate Schwann cell injury response. Interestingly, Sarm1 −/− and Wld s failed to affect macrophage recruitment after injury, while macrophages in injured Wld s nerve stump showed 'nerve scanning' behavior, elongating and extending their process along the distal nerve before fragmentation 70,71 . Lack of spheroids along Wld s axons might contribute to macrophage scanning behavior as they are looking for the potential targets to engulf.…”

Section: Discussionmentioning

confidence: 97%

Regulation of degenerative spheroids after injury

Gamage

Cushman

et al. 2020

Sci Rep

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Neuronal injury leads to rapid, programmed disintegration of axons distal to the site of lesion. Much like other forms of axon degeneration (e.g. developmental pruning, toxic insult from neurodegenerative disorder), Wallerian degeneration associated with injury is preceded by spheroid formation along axons. The mechanisms by which injury leads to formation of spheroids and whether these spheroids have a functional role in degeneration remain elusive. Here, using neonatal mouse primary sympathetic neurons, we investigate the roles of players previously implicated in the progression of Wallerian degeneration in injury-induced spheroid formation. We find that intra-axonal calcium flux is accompanied by actin-Rho dependent growth of calcium rich axonal spheroids that eventually rupture, releasing material to the extracellular space prior to catastrophic axon degeneration. Importantly, after injury, Sarm1−/− and DR6−/−, but not Wlds (excess NAD+) neurons, are capable of forming spheroids that eventually rupture, releasing their contents to the extracellular space to promote degeneration. Supplementation of exogenous NAD+ or expressing WLDs suppresses Rho-dependent spheroid formation and degeneration in response to injury. Moreover, injured or trophically deprived Sarm1−/− and DR6−/−, but not Wlds neurons, are resistant to degeneration induced by conditioned media collected from wild-type axons after spheroid rupture. Taken together, these findings place Rho-actin and NAD+ upstream of spheroid formation and may suggest that other mediators of degeneration, such as DR6 and SARM1, mediate post-spheroid rupture events that lead to catastrophic axon disassembly.

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“…Primary neurons were obtained from dissected mice striatal tissue using a previously described protocol but with some modifications (Tian, Hanson, Canty, Vickers, & King, 2020). Neonatal C57 BL/6 mice (0-24 hr) were decapitated with medical scissors without using anesthetic.…”

Section: Primary Neuron Culturementioning

confidence: 99%

Sirtuin 3 is required for the protective effect of Resveratrol on Manganese‐induced disruption of mitochondrial biogenesis in primary cultured neurons

Sun

Kang

Chen

et al. 2020

Journal of Neurochemistry

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Chronic manganese (Mn) exposure can disturb mitochondrial homeostasis leading to mitochondrial dysfunction, which is involved in Mn‐induced neurodegenerative diseases. Resveratrol (RSV), as a promoter of mitochondrial biogenesis, plays a significant role against mitochondrial dysfunction. However, whether RSV can relieve Mn‐induced neuronal injury and mitochondrial dysfunction remains unknown. Sirtuin 3 (SIRT3), a main mitochondrial sirtuin, is an important regulator of mitochondria to maintain mitochondrial homeostasis. Therefore, this study investigated whether SIRT3 was required for RSV alleviating Mn‐induced mitochondrial dysfunction in primary cultured neurons from C57BL/6 mice. Here, we showed that Mn (100 and 200 μM) exposure for 24 hr caused significant neuronal damage and mitochondrial dysfunction through increasing mitochondrial ROS, reducing mitochondrial membrane potential and adenosine triphosphate level, and leading to mitochondrial network fragmentation, which could be ameliorated by RSV pretreatment in primary cultured neurons. Additionally, our results also indicated that RSV could activate the SIRT1/PGC‐1α signaling pathway and alleviate Mn‐induced disruption of mitochondrial biogenesis by increasing SIRT1 expression and activity, enhancing deacetylation of PGC‐1α. Furthermore, SIRT3 over‐expression increased deacetylation of mitochondrial transcription factor A and mitochondrial DNA (mtDNA) copy number. Oppositely, silencing SIRT3 increased acetylation of mitochondrial transcription factor A and decreased mtDNA copy number. Our results showed SIRT3 was required for the protective effect of RSV in mitochondrial biogenesis. In conclusion, our findings demonstrated that RSV could ameliorate Mn‐induced neuronal injury and mitochondrial dysfunction in primary cultured neurons through activating the SIRT1/ PGC‐1α signaling pathway, and that SIRT3 is required for promoting mitochondrial biogenesis and attenuating Mn‐induced mitochondrial dysfunction.

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Microtubule‐dependent processes precede pathological calcium influx in excitotoxin‐induced axon degeneration

Cited by 10 publications

References 58 publications

Combining Neurobehavioral Analysis and In Vivo Photoaffinity Labeling to Understand Protein Targets of Methamphetamine in Casper Zebrafish

Combining Neurobehavioral Analysis and In Vivo Photoaffinity Labeling to Understand Protein Targets of Methamphetamine in Casper Zebrafish

Regulation of degenerative spheroids after injury

Sirtuin 3 is required for the protective effect of Resveratrol on Manganese‐induced disruption of mitochondrial biogenesis in primary cultured neurons

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