Coordinated stimulation of axon regenerative and neurodegenerative transcriptional programs by Atf4 following optic nerve injury DOI Open Access
Preethi Somasundaram, Madeline M. Farley, Melissa A. Rudy

et al.

Published: May 24, 2023

Previously we showed that neurodegeneration initiated by axonal insults depends in part on the stress-responsive kinase Perk (Larhammar et al., 2017). Here show acts primarily through Activating Transcription Factor-4 (Atf4) to stimulate not only pro-apoptotic but also pro-regenerative responses following optic nerve injury. Using conditional knockout mice, find an extensive Perk/Atf4-dependent transcriptional response includes canonical Atf4 target genes and modest contributions C/ebp homologous protein (Chop). Overlap with c-Jun-dependent transcription suggests interplay a parallel stress pathway couples regenerative apoptotic responses. Accordingly, neuronal of recapitulates neuroprotection afforded deficiency, or impairs axon regeneration enabled disrupting tumor suppressor Pten. These findings contrast functional consequences reported for CRISPR targeting Chop reveal integral role Perk/Atf4 coordinating neurodegenerative CNS

Language: Английский

The interplay of autophagy and oxidative stress in the pathogenesis and therapy of retinal degenerative diseases DOI Creative Commons
Kun‐Che Chang, Pei‐Feng Liu, Chia‐Hsuan Chang

et al.

Cell & Bioscience, Journal Year: 2022, Volume and Issue: 12(1)

Published: Jan. 3, 2022

Oxidative stress is mainly caused by intracellular reactive oxygen species (ROS) production, which highly associated with normal physiological homeostasis and the pathogenesis of diseases, particularly ocular diseases. Autophagy a self-clearance pathway that removes oxidized cellular components regulates ROS levels. can modulate autophagy activity through transcriptional posttranslational mechanisms. further triggers transcription factor activation degrades impaired organelles proteins to eliminate excessive in cells. Thus, may play an antioxidant role protecting cells from oxidative stress. Nevertheless, cause autophagic cell death. In this review, we summarize mechanisms interaction between their roles several including glaucoma, age-related macular degeneration (AMD), diabetic retinopathy (DR), optic nerve atrophy, are major causes blindness. The modulators used treat diseases discussed. findings studies reviewed here might shed light on development use for future treatment

Language: Английский

Citations

107
Recent progress and challenges in the treatment of spinal cord injury DOI Creative Commons
Ting Tian, Sensen Zhang, Maojun Yang

et al.

Protein & Cell, Journal Year: 2023, Volume and Issue: 14(9), P. 635 - 652

Published: Feb. 10, 2023

Abstract Spinal cord injury (SCI) disrupts the structural and functional connectivity between higher center spinal cord, resulting in severe motor, sensory, autonomic dysfunction with a variety of complications. The pathophysiology SCI is complicated multifaceted, thus individual treatments acting on specific aspect or process are inadequate to elicit neuronal regeneration recovery after SCI. Combinatory strategies targeting multiple aspects pathology have achieved greater beneficial effects than therapy alone. Although many problems challenges remain, encouraging outcomes that been preclinical models offer promising foothold for development novel clinical treat In this review, we characterize mechanisms underlying axon adult neurons summarize recent advances facilitating following at both acute chronic stages. addition, analyze current status, remaining problems, realistic towards translation. Finally, consider future treatment provide insights into how narrow translational gap currently exists studies practice. Going forward, trials should emphasize multidisciplinary conversation cooperation identify optimal combinatorial approaches maximize therapeutic benefit humans

Language: Английский

Citations

59
Retinal Ganglion Cell Survival and Axon Regeneration after Optic Nerve Injury: Role of Inflammation and Other Factors DOI Open Access
Kimberly A. Wong, Larry I. Benowitz

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(17), P. 10179 - 10179

Published: Sept. 5, 2022

The optic nerve, like most pathways in the mature central nervous system, cannot regenerate if injured, and within days, retinal ganglion cells (RGCs), neurons that extend axons through begin to die. Thus, there are few clinical options improve vision after traumatic or ischemic nerve injury neurodegenerative diseases such as glaucoma, dominant neuropathy, pathway gliomas. Research over past two decades has identified several strategies enable RGCs entire length of some cases leading modest reinnervation di- mesencephalic visual relay centers. This review primarily focuses on role innate immune system improving RGC survival axon regeneration, its synergy with manipulations signal transduction pathways, transcription factors, cell-extrinsic suppressors growth. this field provides hope clinically effective patients currently untreatable losses could become a reality 5-10 years.

Language: Английский

Citations

39
Retinal Ganglion Cell Transplantation: Approaches for Overcoming Challenges to Functional Integration DOI Creative Commons
Kevin Y. Zhang,

Erika A. Aguzzi,

Thomas V. Johnson

et al.

Cells, Journal Year: 2021, Volume and Issue: 10(6), P. 1426 - 1426

Published: June 8, 2021

As part of the central nervous system, mammalian retinal ganglion cells (RGCs) lack significant regenerative capacity. Glaucoma causes progressive and irreversible vision loss by damaging RGCs their axons, which compose optic nerve. To functionally restore vision, lost must be replaced. Despite tremendous advancements in experimental models neuropathy that have elucidated pathways to induce endogenous RGC neuroprotection axon regeneration, obstacles achieving functional visual recovery through exogenous transplantation remain. Key challenges include poor graft survival, low donor neuron localization host retina, inadequate dendritogenesis synaptogenesis with afferent amacrine bipolar cells. In this review, we summarize current state transplantation, propose a set standard approaches quantifying reporting outcomes order guide collective effort advance field toward replacement nerve regeneration.

Language: Английский

Citations

37
TNIK depletion induces inflammation and apoptosis in injured renal proximal tubule epithelial cells DOI
Shayna T.J. Bradford, Hao Wu, Yuhei Kirita

et al.

AJP Renal Physiology, Journal Year: 2024, Volume and Issue: 326(5), P. F827 - F838

Published: March 14, 2024

In the aftermath of acute kidney injury (AKI), surviving proximal tubule epithelia repopulate injured tubules to promote repair. However, a portion cells fail repair [termed failed-repair (FR-PTCs)] and exert ongoing proinflammatory profibrotic effects. To better understand molecular drivers FR-PTC state, we reanalyzed mouse ischemia-reperfusion single-nucleus RNA-sequencing (snRNA-seq) atlas identify Traf2 Nck interacting kinase (

Language: Английский

Citations

4
CellFIE: Integrating Pathway Discovery With Pooled Profiling of Perturbations Uncovers Pathways of Huntington's Disease, Including Genetic Modifiers of Neuronal Development and Morphology DOI Creative Commons

Byunguk Kang,

Michael Murphy, Christopher Ng

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 20, 2025

Abstract Genomic screens and GWAS are powerful tools for identifying disease-modifying genes, but it is often challenging to understand the pathways by which these genes function. Here, we take an integrated approach that combines network analysis imaging-based pooled genetic perturbation study examine modifiers of Huntington’s disease (HD). The computational highlighted several in a subnetwork enriched neuronal development morphology. To test functional roles developed experimental pipeline allows CRISPRi KD 21 human iPSC-derived neurons followed optical genotypes, arborization, multiplexed pathway activity morphological fingerprint readout. This recovered known involved morphology confirmed unexpected links from between HD Our overcomes challenges measurement function health could be adapted other phenotypes neurological diseases.

Language: Английский

Citations

0
Regulation of the Activity of the Dual Leucine Zipper Kinase by Distinct Mechanisms DOI Creative Commons

Kyra-Alexandra Köster,

Marten Dethlefs, Jorge Duque Escobar

et al.

Cells, Journal Year: 2024, Volume and Issue: 13(4), P. 333 - 333

Published: Feb. 11, 2024

The dual leucine zipper kinase (DLK) alias mitogen-activated protein 3 12 (MAP3K12) has gained much attention in recent years. DLK belongs to the mixed lineage kinases, characterized by homology serine/threonine and tyrosine kinase, but exerts activity. been implicated many diseases, including several neurodegenerative glaucoma, diabetes mellitus. As a MAP3K, it is generally assumed that becomes phosphorylated activated upstream signals phosphorylates activates itself, downstream MAP2K, and, ultimately, MAPK. In addition, other mechanisms such as protein-protein interactions, proteasomal degradation, dephosphorylation various phosphatases, palmitoylation, subcellular localization have shown be involved regulation of activity or its fine-tuning. present review, diverse regulating will summarized provide better insights into action possibly, new targets modulate function.

Language: Английский

Citations

3
Non-Cell-Autonomous Regulation of Optic Nerve Regeneration by Amacrine Cells DOI Creative Commons
Elena G. Sergeeva, Paul A. Rosenberg, Larry I. Benowitz

et al.

Frontiers in Cellular Neuroscience, Journal Year: 2021, Volume and Issue: 15

Published: April 16, 2021

Visual information is conveyed from the eye to brain through axons of retinal ganglion cells (RGCs) that course optic nerve and synapse onto neurons in multiple subcortical visual relay areas. RGCs cannot regenerate their once they are damaged, similar most mature central nervous system (CNS), soon undergo cell death. These phenomena neurodegeneration regenerative failure widely viewed as being determined by cell-intrinsic mechanisms within or be influenced extracellular environment, including glial inflammatory cells. However, a new concept emerging death survival ability also complex circuitry retina activation multicellular signaling cascade involving changes inhibitory interneurons – amacrine (AC) contributes fate RGCs. Here, we review our current understanding role play axon regeneration after injury.

Language: Английский

Citations

15
Inflammatory Mediators of Axon Regeneration in the Central and Peripheral Nervous Systems DOI Open Access
Larry I. Benowitz, Lili Xie, Yuqin Yin

et al.

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(20), P. 15359 - 15359

Published: Oct. 19, 2023

Although most pathways in the mature central nervous system cannot regenerate when injured, research beginning late 20th century has led to discoveries that may help reverse this situation. Here, we highlight recent years from our laboratory identifying oncomodulin (Ocm), stromal cell-derived factor (SDF)-1, and chemokine CCL5 as growth factors expressed by cells of innate immune promote axon regeneration injured optic nerve elsewhere peripheral systems. We also review role ArmC10, a newly discovered Ocm receptor, mediating many these effects, synergy between inflammation-derived complementary strategies regeneration, including deleting genes encoding cell-intrinsic suppressors growth, manipulating transcription suppress or expression growth-related genes, cell-extrinsic growth. In some cases, combinatorial have unprecedented levels regeneration. The identification similar mechanisms human neurons offers hope key made animal models eventually lead treatments improve outcomes after neurological damage patients.

Language: Английский

Citations

6
Regulation of the Activity of the Dual Leucine Zipper Kinase by Distinct Mechanisms DOI Open Access

Kyra-Alexandra Köster,

Marten Dethlefs, Jorge Duque Escobar

et al.

Published: Jan. 4, 2024

The dual leucine zipper kinase (DLK) alias mitogen-activated protein 3 12 (MAP3K12) has gained much attention in recent years. DLK belongs to the mixed lineage kinases, characterized by homology serine/threonine and tyrosine but exerts activity. been implicated many diseases including several neurodegenerative diseases, glaucoma, diabetes mellitus. As a MAP3K, it is generally assumed that becomes phosphorylated activated upstream signals phosphorylates activates itself, downstream MAP2K, ultimately MAPK. In addition, other mechanisms such as protein-protein interactions, proteasomal degradation, dephosphorylation various phosphatases, palmitoylation, subcellular localization have shown be involved regulation of activity or its fine-tuning. present review, diverse regulating will summarized provide better insight into action possibly new targets modulate function.

Language: Английский

Citations

2