The biochemistry of neuronal necrosis: rogue biology?

Syntichaki, Popi; Tavernarakis, Nektarios

doi:10.1038/nrn1174

Cited by 158 publications

(139 citation statements)

References 173 publications

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“…To test the effects of these compounds on regeneration we axotomized mechanosensory neurons of C. elegans. These neurons have been used extensively for investigation of neurodegeneration in connection with human diseases (23,24). They grow long axonal processes devoid of large numbers of lateral branches, enabling highly precise microsurgery and subsequent imaging and characterization of outgrowing processes.…”

Section: Resultsmentioning

confidence: 99%

Large-scale in vivo femtosecond laser neurosurgery screen reveals small-molecule enhancer of regeneration

Samara

Rohde

Gilleland

et al. 2010

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

110

114

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Discovery of molecular mechanisms and chemical compounds that enhance neuronal regeneration can lead to development of therapeutics to combat nervous system injuries and neurodegenerative diseases. By combining high-throughput microfluidics and femtosecond laser microsurgery, we demonstrate for the first time largescale in vivo screens for identification of compounds that affect neurite regeneration. We performed thousands of microsurgeries at single-axon precision in the nematode Caenorhabditis elegans at a rate of 20 seconds per animal. Following surgeries, we exposed the animals to a hand-curated library of approximately one hundred small molecules and identified chemicals that significantly alter neurite regeneration. In particular, we found that the PKC kinase inhibitor staurosporine strongly modulates regeneration in a concentration-and neuronal type-specific manner. Two structurally unrelated PKC inhibitors produce similar effects. We further show that regeneration is significantly enhanced by the PKC activator prostratin. C. elegans | chemical screen | microfluidicsT he ability of neurons in the adult mammalian central nervous system to regenerate their axons after injury is extremely limited, which has been attributed to both extrinsic signals of the inhibitory glial environment (1) as well as intrinsic neuronal factors (2-4). The discovery of cell-permeable small molecules that modulate axon regrowth can potentiate the development of efficient therapeutic treatments for spinal cord injuries, brain trauma, stroke, and neurodegenerative diseases. Identification of such molecules can also provide valuable tools for fundamental investigations of the mechanisms involved in the regeneration process. Currently, small-molecule screens for neuronal regeneration are performed in simple in vitro cell culture systems. Such screens have already revealed large numbers of chemicals that enhance regeneration and/or affect cellular morphogenesis, yet many of these hits still remain untested in vivo. In addition, most in vitro studies do not translate to animal models and also fail to reveal off-target, toxic, or lethal effects. Thus, a thorough investigation of neuronal regeneration mechanisms requires in vivo neuronal injury models.In vivo investigation of neuronal regeneration has been performed mainly in mice and rats. However, their long developmental periods, complicated genetics and biology, and expensive maintenance prevent large-scale studies on these animals. The nematode Caenorhabditis elegans is a simple, well-studied, invertebrate model-organism with a fully mapped neuronal network comprising 302 neurons. Its short developmental cycle, simple and low-cost laboratory maintenance, and genetic amenability make it an ideal model for large-scale screens, rapid identification of the molecular targets of screened compounds, and discovery of novel signaling pathways implicated in regeneration.Until recently however, the small size of C. elegans (∼50 μm in diameter) prevented its use for investigation of neuronal re...

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Section: Resultsmentioning

confidence: 99%

Large-scale in vivo femtosecond laser neurosurgery screen reveals small-molecule enhancer of regeneration

Samara

Rohde

Gilleland

et al. 2010

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

110

114

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“…Specific genetic lesions and environmental conditions trigger necrotic cell death in C. elegans. 12 Dying cells exhibit macroscopic and ultrastructural characteristics reminiscent of necrotic cell death caused by excitotoxic insults and hypoxia that follow ischemic incidents in mammals. 13 We utilized this well-characterized animal model of necrotic cell death to investigate the involvement of autophagy in necrosis.…”

Section: 1mentioning

confidence: 99%

Autophagy is required for necrotic cell death in Caenorhabditis elegans

2007

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Autophagy is the main process for bulk protein and organelle recycling in cells under extracellular or intracellular stress. Deregulation of autophagy has been associated with pathological conditions such as cancer, muscular disorders and neurodegeneration. Necrotic cell death underlies extensive neuronal loss in acute neurodegenerative episodes such as ischemic stroke. We find that excessive autophagosome formation is induced early during necrotic cell death in C. elegans. In addition, autophagy is required for necrotic cell death. Impairment of autophagy by genetic inactivation of autophagy genes or by pharmacological treatment suppresses necrosis. Autophagy synergizes with lysosomal catabolic mechanisms to facilitate cell death. Our findings demonstrate that autophagy contributes to cellular destruction during necrosis. Thus, interfering with the autophagic process may protect neurons against necrotic damage in humans.

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“…22 For example, calcium overload is a pivotal stressor that induces cell death in many human diseases, such as stroke, traumatic brain injury, epilepsy, Alzheimer's disease and glaucoma. [23][24][25] However, much remains to be learned regarding calcium-induced cell death pathways. 26 Here, we reported the discovery of a new type of TLKinduced PCD in Drosophila and delineated the function of TLK in both eye development and calcium-induced cell death.…”

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confidence: 99%

Tousled-like kinase mediated a new type of cell death pathway in Drosophila

et al. 2015

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Programmed cell death (PCD) has an important role in sculpting organisms during development. However, much remains to be learned about the molecular mechanism of PCD. We found that ectopic expression of tousled-like kinase (tlk) in Drosophila initiated a new type of cell death. Furthermore, the TLK-induced cell death is likely to be independent of the canonical caspase pathway and other known caspase-independent pathways. Genetically, atg2 RNAi could rescue the TLK-induced cell death, and this function of atg2 was likely distinct from its role in autophagy. In the developing retina, loss of tlk resulted in reduced PCD in the interommatidial cells (IOCs). Similarly, an increased number of IOCs was present in the atg2 deletion mutant clones. However, double knockdown of tlk and atg2 by RNAi did not have a synergistic effect. These results suggested that ATG2 may function downstream of TLK. In addition to a role in development, tlk and atg2 RNAi could rescue calcium overload-induced cell death. Together, our results suggest that TLK mediates a new type of cell death pathway that occurs in both development and calcium cytotoxicity.

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The biochemistry of neuronal necrosis: rogue biology?

Cited by 158 publications

References 173 publications

Large-scale in vivo femtosecond laser neurosurgery screen reveals small-molecule enhancer of regeneration

Large-scale in vivo femtosecond laser neurosurgery screen reveals small-molecule enhancer of regeneration

Autophagy is required for necrotic cell death in Caenorhabditis elegans

Tousled-like kinase mediated a new type of cell death pathway in Drosophila

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