The Drosophila Cell Corpse Engulfment Receptor Draper Mediates Glial Clearance of Severed Axons

MacDonald, Jennifer M.; Beach, Margaret G.; Porpiglia, Ermelinda; Sheehan, Amy E.; Watts, Ryan J.; Freeman, Marc

doi:10.1016/j.neuron.2006.04.028

Cited by 465 publications

(685 citation statements)

References 59 publications

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“…One possibility is that nucleation of new microtubules plays a structural role. Rebuilding microtubule rods down the center of the dendrite could prevent beading, which is an early step in most types of axon and dendrite degeneration (9,30) In support of this idea, microtubule disassembly has been proposed to be an early step in Wallerian axon degeneration (31,32) and developmental pruning of dendrites (33). In fact, for the developmental pruning pathway, a putative microtubule severing protein is required at an early step (34).…”

Section: Discussionmentioning

confidence: 99%

Axon injury and stress trigger a microtubule-based neuroprotective pathway

Chen

Stone

Tao

et al. 2012

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

102

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Axon injury elicits profound cellular changes, including axon regeneration. However, the full range of neuronal injury responses remains to be elucidated. Surprisingly, after axons of Drosophila dendritic arborization neurons were severed, dendrites were more resistant to injury-induced degeneration. Concomitant with stabilization, microtubule dynamics in dendrites increased. Moreover, dendrite stabilization was suppressed when microtubule dynamics was dampened, which was achieved by lowering levels of the microtubule nucleation protein γ-tubulin. Increased microtubule dynamics and global neuronal stabilization were also activated by expression of expanded polyglutamine (poly-Q) proteins SCA1, SCA3, and huntingtin. In all cases, dynamics were increased through microtubule nucleation and depended on JNK signaling, indicating that acute axon injury and long-term neuronal stress activate a common cytoskeleton-based stabilization program. Reducing levels of γ-tubulin exacerbated long-term degeneration induced by SCA3 in branched sensory neurons and in a well established Drosophila eye model of poly-Q-induced neurodegeneration. Thus, increased microtubule dynamics can delay short-term injury-induced degeneration, and, in the case of poly-Q proteins, can counteract progressive longer-term degeneration. We conclude that axon injury or stress triggers a microtubulebased neuroprotective pathway that stabilizes neurons against degeneration.M any animals generate a single set of neurons that must function for the entire life of the individual. Each neuron typically has a single axon that transmits signals to other neurons or output cells such as muscle. As axons can extend long distances, they are at risk for injury, and, if the single axon is damaged, the cell can no longer function. Many neurons thus mount major responses to axon injury. The best characterized of these responses is axon regeneration, the process in which a neuron extends the stump of the existing axon or grows a new axon from a dendrite (1-3).In addition to the regenerative response, axon injury can cause other less well-understood changes. For example, in mammalian dorsal root ganglion cells, injury of the peripheral axon causes a transcriptional response that increases the capacity of the central axon to regenerate if it is subsequently injured (4, 5). In Drosophila sensory neurons, axon injury causes cytoskeletal changes in the entire dendrite arbor, specifically the number of growing microtubules is up-regulated (6). In this study, we investigated the functional significance of the cytoskeletal changes in the dendrite arbor. We present results that suggest the altered microtubule dynamics in dendrites acts to stabilize them, and thus axon injury seems to trigger a neuroprotective pathway that acts on the rest of the cell. However, this neuroprotective pathway is turned on only transiently after axon injury and subsides as axon regeneration initiates.Axon injury is a very acute neuronal stress. Neurons are also subject to a variety of long-term stress...

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Section: Discussionmentioning

confidence: 99%

Axon injury and stress trigger a microtubule-based neuroprotective pathway

Chen

Stone

Tao

et al. 2012

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

102

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“…1). These findings, and the observations that NMNAT protects from axonal injury 2 , from photoreceptor injury caused by intense light, and that its loss causes massive neurodegeneration 1 , indicate that NMNAT is a versatile neuroprotective agent.…”

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confidence: 81%

“…Conflicting results exist in mammalian systems as to whether Nmnat1 exerts protective effects [13][14][15] and whether NAD is required 4,14,15 . Drosophila contains only one NMNAT gene, whose overexpression delays axonal degeneration 2 . This study and our finding that NMNAT functions as a maintenance factor to protect against activity-induced neurodegeneration 1 suggest that NMNAT alone can protect against multiple neurodegenerative insults.…”

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confidence: 99%

NAD synthase NMNAT acts as a chaperone to protect against neurodegeneration

Zhai

Zhang

Hiesinger³

et al. 2008

Nature

187

218

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Neurodegeneration can be triggered by genetic or environmental factors. Although the precise cause is often unknown, many neurodegenerative diseases share common features such as protein aggregation and age dependence. Recent studies in Drosophila have uncovered protective effects of NAD synthase nicotinamide mononucleotide adenylyltransferase (NMNAT) against activityinduced neurodegeneration and injury-induced axonal degeneration 1,2 . Here we show that NMNAT overexpression can also protect against spinocerebellar ataxia 1 (SCA1)-induced neurodegeneration, suggesting a general neuroprotective function of NMNAT. It protects against neurodegeneration partly through a proteasome-mediated pathway in a manner similar to heatshock protein 70 (Hsp70). NMNAT displays chaperone function both in biochemical assays and cultured cells, and it shares significant structural similarity with known chaperones. Furthermore, it is upregulated in the brain upon overexpression of poly-glutamine expanded protein and recruited with the chaperone Hsp70 into protein aggregates. Our results implicate NMNAT as a stress-response protein that acts as a chaperone for neuronal maintenance and protection. Our studies provide an entry point for understanding how normal neurons maintain activity, and offer clues for the common mechanisms underlying different neurodegenerative conditions. Injury-induced axonal degeneration is dramatically delayed in wallerian degeneration slow (Wld S ) mice, a mutant strain that over-expresses a chimaeric protein containing the NAD synthase NMNAT 3,4 . The Wld S chimaeric protein offers neuroprotection against axonal degeneration 2,5-7 as well as a variety of neurodegenerative conditions [8][9][10][11] . Wld S protein contains the amino (N)-terminal 70-amino-acid fragment of ubiquitination factor E4B ©2008 Nature Publishing GroupCorrespondence and requests for materials should be addressed to R.G. 4,14,15 . Drosophila contains only one NMNAT gene, whose overexpression delays axonal degeneration 2 . This study and our finding that NMNAT functions as a maintenance factor to protect against activity-induced neurodegeneration 1 suggest that NMNAT alone can protect against multiple neurodegenerative insults. Our recent finding that enzymatically inactive NMNAT retains neuroprotective capabilities also exposed a hitherto unknown molecular function 1 .To test if NMNAT is a general factor required for neuronal maintenance and protection, we first examined the effects of NMNAT overexpression in a Drosophila model for SCA1. Overexpression of wild-type NMNAT or enzyme-inactive NMNAT (NMNAT-WR) 1 suppresses the degenerative phenotypes induced by overexpression of Drosophila ataxin-1 (dAtx-1). It also offers moderate protection against the severe phenotypes caused by overexpression of human ataxin-1 with an expanded (82) poly-glutamine tract (hAtx-1[82Q]) 16 (Fig. 1). These findings, and the observations that NMNAT protects from axonal injury 2 , from photoreceptor injury caused by intense light, and that its loss c...

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“…In vivo protective effect of the Wld S protein has also been demonstrated in different species. For example, it was also found to protect physically injured axons in transgenic rats , as well as surgically severed Drosophila olfactory receptor neurons (ORN) (Hoopfer et al, 2006;MacDonald et al, 2006). In addition, the Wld S is able to protect axon degeneration in other disease models (reviewed by Coleman et al, 2005, also see below).…”

Section: Wld S As a Model To Study The Mechanisms Of Axon Degenerationmentioning

confidence: 99%

WldS, Nmnats and axon degeneration-progress in the past two decades

Yan

et al. 2010

Protein Cell

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A chimeric protein called Wallerian degeneration slow (Wld S ) was first discovered in a spontaneous mutant strain of mice that exhibited delayed Wallerian degeneration. This provides a useful tool in elucidating the mechanisms of axon degeneration. Over-expression of Wld S attenuates the axon degeneration that is associated with several neurodegenerative disease models, suggesting a new logic for developing a potential protective strategy. At molecular level, although Wld S is a fusion protein, the nicotinamide mononucleotide adenylyl transferase 1 (Nmnat1) is required and sufficient for the protective effects of Wld S , indicating a critical role of NAD biosynthesis and perhaps energy metabolism in axon degeneration. These findings challenge the proposed model in which axon degeneration is operated by an active programmed process and thus may have important implication in understanding the mechanisms of neurodegeneration. In this review, we will summarize these recent findings and discuss their relevance to the mechanisms of axon degeneration.

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The Drosophila Cell Corpse Engulfment Receptor Draper Mediates Glial Clearance of Severed Axons

Cited by 465 publications

References 59 publications

Axon injury and stress trigger a microtubule-based neuroprotective pathway

Axon injury and stress trigger a microtubule-based neuroprotective pathway

NAD synthase NMNAT acts as a chaperone to protect against neurodegeneration

WldS, Nmnats and axon degeneration-progress in the past two decades

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