Axonal injury signaling is restrained by a spared synaptic branch DOI Open Access
Laura J. Smithson, Juliana Zang, Lucas Junginger

et al.

Published: Dec. 27, 2024

The intrinsic ability of injured neurons to degenerate and regenerate their axons facilitates nervous system repair, however this is not engaged in all injury locations. Here we investigate the regulation a conserved axonal response pathway with respect location damage branched motoneuron Drosophila larvae. dileucine zipper kinase DLK, (also known as MAP3K12 mammals Wallenda (Wnd) ), key regulator diverse responses injury. In three different populations motoneurons, observed same striking result that Wnd/DLK signaling becomes activated only injuries remove synaptic terminals. Injuries spare even small part terminal fail activate signaling, despite presence extensive degeneration. injury-induced occurs independently its previously regulator, Hiw/PHR ubiquitin ligase. We propose linked trafficking synapse-to-nucleus cargo mechanism enables respond impairments connectivity.

Language: Английский

Injury distance limits the transcriptional response to spinal injury DOI Creative Commons
Zimei Wang,

Manojkumar Kumaran,

Elizabeth Batsel

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: June 1, 2024

Abstract The ability of neurons to sense and respond damage is fundamental homeostasis nervous system repair. For some cell types, notably dorsal root ganglia (DRG) retinal ganglion cells (RGCs), extensive profiling has revealed a large transcriptional response axon injury that determines survival regenerative outcomes. In contrast, the most supraspinal whose limited regeneration constrains recovery from spinal injury, mostly unknown. Here we employed single-nuclei sequencing in mice profile responses diverse types injury. Surprisingly, thoracic triggered only modest changes gene expression across all populations, including corticospinal tract (CST) neurons. Moreover, CST also responded minimally cervical but much more strongly intracortical axotomy, upregulation numerous apoptosis-related transcripts shared with injured DRG RGC Thus, muted neuron linked injury’s distal location, rather than intrinsic cellular characteristics. More broadly, these findings indicate central challenge for enhancing after sensing distant injuries subsequent baseline neuronal response.

Language: Английский

Citations

6
Neural regeneration in the human central nervous system—from understanding the underlying mechanisms to developing treatments. Where do we stand today? DOI Creative Commons
Christopher Elnan Kvistad, Torbjørn Kråkenes, Sonia Gavasso

et al.

Frontiers in Neurology, Journal Year: 2024, Volume and Issue: 15

Published: May 9, 2024

Mature neurons in the human central nervous system (CNS) fail to regenerate after injuries. This is a common denominator across different aetiologies, including multiple sclerosis, spinal cord injury and ischemic stroke. The lack of regeneration leads permanent functional deficits with substantial impact on patient quality life, representing significant socioeconomic burden worldwide. Great efforts have been made decipher responsible mechanisms we now know that potent intra- extracellular barriers prevent axonal repair. knowledge has resulted numerous clinical trials, aiming promote neuroregeneration through approaches. Here, summarize current understanding causes poor within CNS. We also review results treatment attempts translated into trials so far.

Language: Английский

Citations

5
Translatome analysis reveals cellular network in DLK-dependent hippocampal glutamatergic neuron degeneration DOI Open Access
Erin M Ritchie,

Dilan Acar,

Siming Zhong

et al.

Published: Feb. 6, 2025

The conserved MAP3K12/Dual Leucine Zipper Kinase (DLK) plays versatile roles in neuronal development, axon injury and stress responses, neurodegeneration, depending on cell-type cellular contexts. Emerging evidence implicates abnormal DLK signaling several neurodegenerative diseases. However, our understanding of the DLK-dependent gene network central nervous system remains limited. Here, we investigated hippocampal glutamatergic neurons using conditional knockout induced overexpression mice. We found that dorsal CA1 dentate gyrus are vulnerable to elevated expression DLK, while CA3 appear less vulnerable. identified translatome includes molecular signatures displays specificity. Increasing is associated with disruptions microtubules, potentially involving STMN4. Additionally, primary cultured expressing different levels show altered neurite outgrowth, specification, synapse formation. identification translational targets has relevance selective neuron vulnerability under pathological conditions.

Language: Английский

Citations

0
Translatome analysis reveals cellular network in DLK-dependent hippocampal glutamatergic neuron degeneration DOI Creative Commons
Erin M Ritchie,

Dilan Acar,

Siming Zhong

et al.

eLife, Journal Year: 2025, Volume and Issue: 13

Published: March 11, 2025

The conserved MAP3K12/Dual Leucine Zipper Kinase (DLK) plays versatile roles in neuronal development, axon injury and stress responses, neurodegeneration, depending on cell-type cellular contexts. Emerging evidence implicates abnormal DLK signaling several neurodegenerative diseases. However, our understanding of the DLK-dependent gene network central nervous system remains limited. Here, we investigated hippocampal glutamatergic neurons using conditional knockout induced overexpression mice. We found that dorsal CA1 dentate gyrus are vulnerable to elevated expression DLK, while CA3 appear less vulnerable. identified translatome includes molecular signatures displays specificity. Increasing is associated with disruptions microtubules, potentially involving STMN4. Additionally, primary cultured expressing different levels show altered neurite outgrowth, specification, synapse formation. identification translational targets has relevance selective neuron vulnerability under pathological conditions.

Language: Английский

Citations

0
Axonal injury signaling is restrained by a spared synaptic branch DOI Open Access
Laura J. Smithson, Juliana Zang, Lucas Junginger

et al.

Published: March 18, 2025

The intrinsic ability of injured neurons to degenerate and regenerate their axons facilitates nervous system repair, however this is not engaged in all injury locations. Here we investigate the regulation a conserved axonal response pathway with respect location damage branched motoneuron Drosophila larvae. dileucine zipper kinase DLK, (also known as MAP3K12 mammals Wallenda (Wnd) ), key regulator diverse responses injury. In three different populations motoneurons, observed same striking result that Wnd/DLK signaling becomes activated only injuries remove synaptic terminals. Injuries spare even small part terminal fail activate signaling, despite presence extensive degeneration. injury-induced occurs independently its previously regulator, Hiw/PHR ubiquitin ligase. We propose linked trafficking synapse-to-nucleus cargo mechanism enables respond impairments connectivity.

Language: Английский

Citations

0
Inhibiting acute, axonal DLK palmitoylation is neuroprotective and avoids deleterious effects of cell-wide DLK inhibition DOI Creative Commons
Xiaotian Zhang,

Hey‐Kyeong Jeong,

Jingwen Niu

et al.

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: April 3, 2025

Language: Английский

Citations

0
Microtubules, Membranes, and Movement: New Roles for Stathmin‐2 in Axon Integrity DOI Creative Commons
Emma J. C. Thornburg‐Suresh, Daniel W. Summers

Journal of Neuroscience Research, Journal Year: 2024, Volume and Issue: 102(9)

Published: Sept. 1, 2024

Neurons establish functional connections responsible for how we perceive and react to the world around us. Communication from a neuron its target cell occurs through long projection called an axon. Axon distances can exceed 1 m in length humans require dynamic microtubule cytoskeleton growth during development maintenance adulthood. Stathmins are microtubule-associated proteins that function as relays between kinase signaling polymerization. In this review, describe prolific role of homeostasis with emphasis on emerging roles Stathmin-2 (Stmn2) axon integrity neurodegeneration. Stmn2 levels altered Amyotrophic Lateral Sclerosis loss provokes motor sensory neuropathies. There is growing potential employing disease biomarker or even therapeutic target. Meeting requires mechanistic understanding complexity function. particular, palmitoylation has surprising contribution undefined mechanisms linking membrane association, tubulin interaction, transport. Exploring these will reveal new insight neuronal biology novel opportunities intervention.

Language: Английский

Citations

1
Axonal injury signaling is restrained by a spared synaptic branch DOI Creative Commons
Laura J. Smithson, Juliana Zang, Lucas Junginger

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 7, 2024

Abstract The intrinsic ability of injured neurons to degenerate and regenerate their axons facilitates nervous system repair, however this is not engaged in all injury locations. Here we investigate the regulation a conserved axonal response pathway with respect location damage branched motoneuron Drosophila larvae. dileucine zipper kinase DLK, (also known as MAP3K12 mammals Wallenda (Wnd) ), key regulator diverse responses injury. In three different populations motoneurons, observed same striking result that Wnd/DLK signaling becomes activated only injuries remove synaptic terminals. Injuries spare even small part terminal fail activate signaling, despite presence extensive degeneration. injury-induced occurs independently its previously regulator, Hiw/PHR ubiquitin ligase. We propose linked trafficking synapse-to-nucleus cargo mechanism enables respond impairments connectivity.

Language: Английский

Citations

1
Translatome analysis reveals cellular network in DLK-dependent hippocampal glutamatergic neuron degeneration DOI Creative Commons
Erin M Ritchie,

Dilan Acar,

Siming Zhong

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: July 12, 2024

Abstract The conserved MAP3K12/Dual Leucine Zipper Kinase (DLK) plays versatile roles in neuronal development, axon injury and stress responses, neurodegeneration, depending on cell-type cellular contexts. Emerging evidence implicates abnormal DLK signaling several neurodegenerative diseases. However, our understanding of the DLK-dependent gene network central nervous system remains limited. Here, we investigated hippocampal glutamatergic neurons using conditional knockout induced overexpression mice. We found that dorsal CA1 dentate gyrus are vulnerable to elevated expression DLK, while CA3 appear less vulnerable. identified translatome includes molecular signatures displays specificity. Increasing is associated with disruptions microtubules, potentially involving STMN4. Additionally, primary cultured expressing different levels show altered neurite outgrowth, specification, synapse formation. identification translational targets has relevance selective neuron vulnerability under pathological conditions.

Language: Английский

Citations

0
Translatome analysis reveals cellular network in DLK-dependent hippocampal glutamatergic neuron degeneration DOI Creative Commons
Erin M Ritchie,

Dilan Acar,

Siming Zhong

et al.

eLife, Journal Year: 2024, Volume and Issue: 13

Published: Sept. 10, 2024

The conserved MAP3K12/Dual Leucine Zipper Kinase (DLK) plays versatile roles in neuronal development, axon injury and stress responses, neurodegeneration, depending on cell-type cellular contexts. Emerging evidence implicates abnormal DLK signaling several neurodegenerative diseases. However, our understanding of the DLK-dependent gene network central nervous system remains limited. Here, we investigated hippocampal glutamatergic neurons using conditional knockout induced overexpression mice. We found that dorsal CA1 dentate gyrus are vulnerable to elevated expression DLK, while CA3 appear less vulnerable. identified translatome includes molecular signatures displays specificity. Increasing is associated with disruptions microtubules, potentially involving STMN4. Additionally, primary cultured expressing different levels show altered neurite outgrowth, specification, synapse formation. identification translational targets has relevance selective neuron vulnerability under pathological conditions.

Language: Английский

Citations

0