The synaptic vesicle SNARE neuronal Synaptobrevin promotes endolysosomal degradation and prevents neurodegeneration

Haberman, Adam; Williamson, W. Ryan; Epstein, Daniel; Wang, Dong; Rina, Srisha; Meinertzhagen, Ian A.; Hiesinger, P. Robin

doi:10.1083/jcb.201108088

Cited by 46 publications

(62 citation statements)

References 50 publications

(108 reference statements)

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“…These results are also consistent with a recent study demonstrating that loss of nSyb in Drosophila photoreceptors causes degeneration that is independent of synaptic transmission defects (Haberman et al 2012). Together, these data suggest that the neurodegeneration observed in comt mutants is likely to involve a mechanism other than synaptic transmission.…”

Section: Resultssupporting

confidence: 81%

“…comt mutants display stress-induced locomotor defects, severely shortened lifespan, and neurodegeneration. This neurodegeneration is apparently independent of the role of NSF1 in synaptic transmission similar to what has been observed in nSyb mutants (Haberman et al 2012). Autophagy is disrupted in comt mutants, due at least in part to a defect in trafficking of cathepsin-L to lysosomes.…”

Section: Discussionmentioning

confidence: 49%

“…Matching SNARE proteins to a particular fusion could be complex, however. As illustrated by the recent characterization of retinal degeneration in nSyb mutants in flies (Haberman et al 2012), there is precedent for the same SNARE complex proteins independently mediating various distinct fusion events.…”

Section: Discussionmentioning

confidence: 99%

“…However, recent evidence demonstrates that SNARE proteins such as neuronal synaptobrevin (nSyb) have important neuroprotective functions in addition to mediating synaptic transmission (Haberman et al 2012). Nonetheless, the question of whether recycling of SNARE complexes following fusion and its dependence on NSF1 is as important for these neuroprotective functions as for rapid transmitter release in synaptic transmission has not previously been addressed.…”

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confidence: 99%

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A Neuroprotective Function of NSF1 Sustains Autophagy and Lysosomal Trafficking inDrosophila

2014

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A common feature of many neurodegenerative diseases is the accumulation of toxic proteins that disrupt vital cellular functions. Degradative pathways such as autophagy play an important protective role in breaking down misfolded and long-lived proteins. Neurons are particularly vulnerable to defects in these pathways, but many of the details regarding the link between autophagy and neurodegeneration remain unclear. We previously found that temperature-sensitive paralytic mutants in Drosophila are enriched for those exhibiting age-dependent neurodegeneration. Here we show that one of these mutants, comatose (comt), in addition to locomotor defects, displays shortened lifespan and progressive neurodegeneration, including loss of dopaminerigic (DA) neurons. comt encodes Nethyl-maleimide sensitive fusion protein (NSF1), which has a well-documented role in synaptic transmission. However, the neurodegenerative phenotypes we observe in comt mutants do not appear to depend on defects in synaptic transmission, but rather from their inability to sustain autophagy under stress, due at least in part to a defect in trafficking of lysosomal proteases such as cathepsin-L. Conversely, overexpression of NSF1 rescues a-synuclein-induced toxicity of DA neurons in a model of Parkinson's disease. Our results demonstrate a neuroprotective role for NSF1 that involves mediation of fusion events crucial for degradative pathways such as autophagy, providing greater understanding of cellular dysfunctions common to several neurodegenerative diseases.

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Section: Resultssupporting

confidence: 81%

Section: Discussionmentioning

confidence: 49%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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A Neuroprotective Function of NSF1 Sustains Autophagy and Lysosomal Trafficking inDrosophila

2014

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“…For example, loss of neuronspecific synaptic v-SNARE (soluble NSF attachment protein receptor) n-syb (neuronal Synaptobrevin) leads to increased autophagic activity in adult D. melanogaster photoreceptor neurons [54] . Such enhancement of autophagy is proposed to be a consequence of primary vesicle traffi cking defects [54] . Snapin, initially identifi ed as a neuronal SNARE-binding protein, is a crucial modulator of vesicle release and presynaptic homeostatic plasticity [55,56] .…”

Section: Autophagy and Synaptic Regulatorsmentioning

confidence: 99%

Autophagy in synaptic development, function, and pathology

et al. 2015

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In the nervous system, neurons contact each other to form neuronal circuits and drive behavior, relying heavily on synaptic connections. The proper development and growth of synapses allows functional transmission of electrical information between neurons or between neurons and muscle fi bers. Defects in synapse-formation or development lead to many diseases. Autophagy, a major determinant of protein turnover, is an essential process that takes place in developing synapses. During the induction of autophagy, proteins and cytoplasmic components are encapsulated in autophagosomes, which fuse with lysosomes to form autolysosomes. The cargoes are subsequently degraded and recycled. However, aberrant autophagic activity may lead to synaptic dysfunction, which is a common pathological characteristic in several disorders. Here, we review the current understanding of autophagy in regulating synaptic development and function. In addition, autophagy-related synaptic dysfunction in human diseases is also summarized.

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The where, what, and when of membrane protein degradation in neurons

Jin

Kiral

Hiesinger

2017

Developmental Neurobiology

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Membrane protein turnover and degradation are required for the function and health of all cells. Neurons may live for the entire lifetime of an organism and are highly polarized cells with spatially segregated axonal and dendritic compartments. Both longevity and morphological complexity represent challenges for regulated membrane protein degradation. To investigate how neurons cope with these challenges, an increasing number of recent studies investigated local, cargo‐specific protein sorting, and degradation at axon terminals and in dendritic processes. In this review, we explore the current answers to the ensuing questions of where, what, and when membrane proteins are degraded in neurons. © 2017 The Authors Developmental Neurobiology Published by Wiley Periodicals, Inc. Develop Neurobiol 78: 283–297, 2018

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The synaptic vesicle SNARE neuronal Synaptobrevin promotes endolysosomal degradation and prevents neurodegeneration

Abstract: The synaptic v-SNARE n-Syb functions not only in synaptic vesicle exocytosis but also in delivery of protein-degrading enzymes to endosomes that are necessary to prevent protein aggregation and neurodegeneration.

Cited by 46 publications

References 50 publications

A Neuroprotective Function of NSF1 Sustains Autophagy and Lysosomal Trafficking inDrosophila

A Neuroprotective Function of NSF1 Sustains Autophagy and Lysosomal Trafficking inDrosophila

Autophagy in synaptic development, function, and pathology

The where, what, and when of membrane protein degradation in neurons

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