A presynaptic endosomal trafficking pathway controls synaptic growth signaling

Department of Biology, The Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
The Journal of Cell Biology (Impact Factor: 9.83). 04/2011; 193(1):201-17. DOI: 10.1083/jcb.201009052
Source: PubMed


Structural remodeling of synapses in response to growth signals leads to long-lasting alterations in neuronal function in many systems. Synaptic growth factor receptors alter their signaling properties during transit through the endocytic pathway, but the mechanisms controlling cargo traffic between endocytic compartments remain unclear. Nwk (Nervous Wreck) is a presynaptic F-BAR/SH3 protein that regulates synaptic growth signaling in Drosophila melanogaster. In this paper, we show that Nwk acts through a physical interaction with sorting nexin 16 (SNX16). SNX16 promotes synaptic growth signaling by activated bone morphogenic protein receptors, and live imaging in neurons reveals that SNX16-positive early endosomes undergo transient interactions with Nwk-containing recycling endosomes. We identify an alternative signal termination pathway in the absence of Snx16 that is controlled by endosomal sorting complex required for transport (ESCRT)-mediated internalization of receptors into the endosomal lumen. Our results define a presynaptic trafficking pathway mediated by SNX16, NWK, and the ESCRT complex that functions to control synaptic growth signaling at the interface between endosomal compartments.

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    • "These studies have focused on Nwk-dependent attenuation of NMJ growth and have demonstrated that Nwk negatively regulates a retrograde (muscle to neuron) BMP growth signal in concert with endocytic proteins Dap160/ intersectin, Shibire/dynamin, Endophilin and Sorting Nexin 16 (Snx16) (Coyle et al., 2004; O'Connor-Giles et al., 2008; Rodal et al., 2011, 2008). Genetic interactions with the Wingless/Wnt signaling pathway indicate that the role of Nwk in the intracellular modulation of growth signaling at the NMJ extends to multiple pathways (Rodal et al., 2011). "
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    ABSTRACT: Nervous wreck (Nwk) is a conserved F-BAR protein that attenuates synaptic growth and promotes synaptic function in Drosophila. In an effort to understand how Nwk carries out its dual roles, we isolated interacting proteins through mass spectrometry. We report a conserved interaction between Nwk proteins and BAR-SH3 Sorting nexins, a family of membrane-binding proteins implicated in diverse intracellular trafficking processes. In mammalian cells, BAR-SH3 Sorting nexins induce plasma membrane tubules that colocalize Nwk2, consistent with a possible functional interaction during early stages of endocytic trafficking. To study the role of BAR-SH3 Sorting nexins in vivo, we took advantage of the lack of genetic redundancy in Drosophila and employed CRISPR-based genome engineering to generate null and endogenously tagged alleles of SH3PX1. SH3PX1 localizes to neuromuscular junctions where it regulates synaptic ultrastructure, but not synapse number. Consistently, neurotransmitter release is significantly diminished in SH3PX1 mutants. Double mutant and tissue-specific rescue experiments indicate that SH3PX1 promotes neurotransmitter release presynaptically, at least in part through functional interactions with Nwk, and may act to distinguish Nwk's roles in regulating synaptic growth and function.
    Preview · Article · Nov 2015 · Journal of Cell Science
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    • "Disruption of endosomal traffic has been shown to be a major mechanism in the generation of synapse overgrowth driven by aberrant TGF- signaling at the Drosophila NMJ (Sweeney and Davis, 2002; Wang et al., 2007; O'Connor-Giles et al., 2008; Rodal et al., 2011; Shi et al., 2013; Vanlandingham et al., 2013). "
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    ABSTRACT: Mutations in genes essential for protein homeostasis have been identified in frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) patients. Why mature neurons should be particularly sensitive to such perturbations is unclear. We identified mutations in Rab8 in a genetic screen for enhancement of an FTD phenotype associated with ESCRT-III dysfunction. Examination of Rab8 mutants or motor neurons expressing a mutant ESCRT-III subunit, CHMP2B(Intron5), at the Drosophila melanogaster neuromuscular junction synapse revealed synaptic overgrowth and endosomal dysfunction. Expression of Rab8 rescued overgrowth phenotypes generated by CHMP2B(Intron5). In Rab8 mutant synapses, c-Jun N-terminal kinase (JNK)/activator protein-1 and TGF-β signaling were overactivated and acted synergistically to potentiate synaptic growth. We identify novel roles for endosomal JNK-scaffold POSH (Plenty-of-SH3s) and a JNK kinase kinase, TAK1, in regulating growth activation in Rab8 mutants. Our data uncover Rab8, POSH, and TAK1 as regulators of synaptic growth responses and point to recycling endosome as a key compartment for synaptic growth regulation during neurodegenerative processes. © 2015 West et al.
    Full-text · Article · Mar 2015 · The Journal of Cell Biology
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    • "In tissue culture cells, overexpressed BACE1 mainly resides in acidic compartments (TGN, endosomes) where BACE1 substrate cleavage occurs. Endosomes within presynaptic terminals have been reported [42, 87, 110] and although they have not been extensively studied, evidence suggests that presynaptic endosomes are involved in neurotransmitter vesicle recycling [10, 28, 35, 82, 86]. Further investigation of presynaptic endosomes may reveal the role of BACE1 within this compartment, which may reflect the need for proteolytic processing of one or more BACE1 substrates at or near the synapse. "
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    ABSTRACT: β-Site amyloid precursor protein (APP) cleaving enzyme-1 (BACE1) is the β-secretase that initiates Aβ production in Alzheimer’s disease (AD). BACE1 levels are increased in AD, which could contribute to pathogenesis, yet the mechanism of BACE1 elevation is unclear. Furthermore, the normal function of BACE1 is poorly understood. We localized BACE1 in the brain at both the light and electron microscopic levels to gain insight into normal and pathophysiologic roles of BACE1 in health and AD, respectively. Our findings provide the first ultrastructural evidence that BACE1 localizes to vesicles (likely endosomes) in normal hippocampal mossy fiber terminals of both non-transgenic and APP transgenic (5XFAD) mouse brains. In some instances, BACE1-positive vesicles were located near active zones, implying a function for BACE1 at the synapse. In addition, BACE1 accumulated in swollen dystrophic autophagosome-poor presynaptic terminals surrounding amyloid plaques in 5XFAD cortex and hippocampus. Importantly, accumulations of BACE1 and APP co-localized in presynaptic dystrophies, implying increased BACE1 processing of APP in peri-plaque regions. In primary cortical neuron cultures, treatment with the lysosomal protease inhibitor leupeptin caused BACE1 levels to increase; however, exposure of neurons to the autophagy inducer trehalose did not reduce BACE1 levels. This suggests that BACE1 is degraded by lysosomes but not by autophagy. Our results imply that BACE1 elevation in AD could be linked to decreased lysosomal degradation of BACE1 within dystrophic presynaptic terminals. Elevated BACE1 and APP levels in plaque-associated presynaptic dystrophies could increase local peri-plaque Aβ generation and accelerate amyloid plaque growth in AD. Electronic supplementary material The online version of this article (doi:10.1007/s00401-013-1152-3) contains supplementary material, which is available to authorized users.
    Full-text · Article · Jul 2013 · Acta Neuropathologica
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