Guidance Receptor Degradation Is Required for Neuronal Connectivity in the Drosophila Nervous System

University of Cambridge, United Kingdom
PLoS Biology (Impact Factor: 9.34). 12/2010; 8(12):e1000553. DOI: 10.1371/journal.pbio.1000553
Source: PubMed

ABSTRACT Author Summary
Brain wiring is determined by genetic and environmental factors, nature and nurture. The Drosophila brain is a model for the genetic basis of brain wiring. The fly visual system in particular is thought to be “hard-wired,” i.e., encoded solely by a genetic program. Some key genes encode the guidance receptors that serve as “wiring” and synaptic connectivity signals. However, it is poorly understood how guidance receptors are spatiotemporally regulated to serve as meaningful synapse formation signals. Indeed, many genes required for brain wiring do not encode the guidance receptors themselves, but rather encode parts of the cell biological machinery that governs their spatiotemporal signaling dynamics. For example, the vesicular ATPase is an intracellular sorting and acidification complex involved in regulating guidance receptor turnover and signaling. The protein V100 is a member of this v-ATPase complex, and in this study we show that mutations in the v100 gene cause brain wiring defects specifically in the adult brain. We further describe a V100-dependent intracellular “sort-and-degrade” mechanism that is required in neurons, and find that when this mechanism is perturbed, it leads to progressive build-up of and aberrant signaling by guidance receptors. These data suggest that a v100-dependent neuronal degradation mechanism provides a cell biological basis for guidance receptor turnover and spatiotemporally controlled dynamics during neural circuit formation.

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    • "mSnf7-2 also binds to CHMP2B, an ESCRT-III subunit for which mutations have been found to cause a rare form of Frontotemporal Dementia [39,58], as discussed in the next section. Similarly, acidification defects lead to aberrant endosomal accumulations and can cause slow neuronal degeneration [59-62]. Intracompartmental acidification regulates the function of synaptic vesicles and endosomal compartments [63,64]. "
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    ABSTRACT: Most neurons are born with the potential to live for the entire lifespan of the organism. In addition, neurons are highly polarized cells with often long axons, extensively branched dendritic trees and many synaptic contacts. Longevity together with morphological complexity results in a formidable challenge to maintain synapses healthy and functional. This challenge is often evoked to explain adult-onset degeneration in numerous neurodegenerative disorders that result from otherwise divergent causes. However, comparably little is known about the basic cell biological mechanisms that keep normalsynapses alive and functional in the first place. How the basic maintenance mechanisms are related to slow adult-onset degeneration in different diseasesis largely unclear. In this review we focus on two basic and interconnected cell biological mechanisms that are required for synaptic maintenance: endomembrane recycling and calcium (Ca2+) homeostasis. We propose that subtle defects in these homeostatic processes can lead to late onset synaptic degeneration. Moreover, the same basic mechanisms are hijacked, impaired or overstimulated in numerous neurodegenerative disorders. Understanding the pathogenesis of these disorders requires an understanding of both the initial cause of the disease and the on-going changes in basic maintenance mechanisms. Here we discuss the mechanisms that keep synapses functional over long periods of time with the emphasis on their role in slow adult-onset neurodegeneration.
    Molecular Neurodegeneration 07/2013; 8(1):23. DOI:10.1186/1750-1326-8-23 · 6.56 Impact Factor
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    • "Mutations in v0a1 (v100 in Drosophila) lead to neuron-specific degradation defects and are, to our knowledge, the first mutations in a neuron-specific regulator of membrane trafficking shown to cause neurodegeneration. Loss of v100 causes intracellular sorting and degradation defects downstream of endocytosis [29, 30]. Similarly, mutations in the synaptic vesicle SNARE neuronal Synaptobrevin (n-syb) cause intracellular sorting and degradation defects that lead to slow adult-onset degeneration in Drosophila [31]. "
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    ABSTRACT: Defects in membrane trafficking and degradation are hallmarks of most, and maybe all, neurodegenerative disorders. Such defects typically result in the accumulation of undegraded proteins due to aberrant endosomal sorting, lysosomal degradation, or autophagy. The genetic or environmental cause of a specific disease may directly affect these membrane trafficking processes. Alternatively, changes in intracellular sorting and degradation can occur as cellular responses of degenerating neurons to unrelated primary defects such as insoluble protein aggregates or other neurotoxic insults. Importantly, altered membrane trafficking may contribute to the pathogenesis or indeed protect the neuron. The observation of dramatic changes to membrane trafficking thus comes with the challenging need to distinguish pathological from protective alterations. Here, we will review our current knowledge about the protective and destructive roles of membrane trafficking in neuronal maintenance and degeneration. In particular, we will first focus on the question of what type of membrane trafficking keeps healthy neurons alive in the first place. Next, we will discuss what alterations of membrane trafficking are known to occur in Alzheimer's disease and other tauopathies, Parkinson's disease, polyQ diseases, peripheral neuropathies, and lysosomal storage disorders. Combining the maintenance and degeneration viewpoints may yield insight into how to distinguish when membrane trafficking functions protectively or contributes to degeneration.
    Cellular and Molecular Life Sciences CMLS 11/2012; 70(16). DOI:10.1007/s00018-012-1201-4 · 5.81 Impact Factor
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    • "High-resolution light microscopy was performed using a Confocal Microscope (Leica SP5). Imaging data was processed and quantified using Amira 5.2 (Indeed, Berlin, Germany) and Adobe Photoshop CS4 as described in [24]. The following antibodies were used at 1∶500: rabbit anti-rab5, rabbit anti-rab7 [25], mouse anti-rab11. "
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    ABSTRACT: We recently generated rab-Gal4 lines for 25 of 29 predicted Drosophila rab GTPases. These lines provide tools for the expression of reporters, mutant rab variants or other genes, under control of the regulatory elements of individual rab loci. Here, we report the generation and characterization of the remaining four rab-Gal4 lines. Based on the completed 'rab-Gal4 kit' we performed a comparative analysis of the cellular and subcellular expression of all rab GTPases. This analysis includes the cellular expression patterns in characterized neuronal and non-neuronal cells and tissues, the subcellular localization of wild type, constitutively active and dominant negative rab GTPases and colocalization with known intracellular compartment markers. Our comparative analysis identifies all Rab GTPases that are expressed in the same cells and localize to the same intracellular compartments. Remarkably, similarities based on these criteria are typically not predicted by primary sequence homology. Hence, our findings provide an alternative basis to assess potential roles and redundancies based on expression in developing and adult cell types, compartment identity and subcellular localization.
    PLoS ONE 07/2012; 7(7):e40912. DOI:10.1371/journal.pone.0040912 · 3.23 Impact Factor
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