Rab3-GEF Controls Active Zone Development at the<i>Drosophila</i>Neuromuscular Junction

Bae, Haneui; Chen, Shirui; Roche, John P.; Ai, Minrong; Wu, Chunlai; DiAntonio, Aaron; Graf, Ethan R.

doi:10.1523/eneuro.0031-16.2016

Cited by 13 publications

(12 citation statements)

References 47 publications

(98 reference statements)

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“…We observed that liprin-α mutant NMJs contain a large portion of unapposed GluRIII-labeled PSDs ( Figure 5G ), resembling the defects in unc-104 mutants. Similar defects were reported for rab3 and rab3-gef mutants ( Bae et al, 2016 ; Graf et al, 2009 ). However, in contrast to unc-104 , the liprin-α and rab3 synaptic defects were not suppressed by mutations in wnd ( Figure 5G–I ).…”

Section: Resultssupporting

confidence: 85%

Restraint of presynaptic protein levels by Wnd/DLK signaling mediates synaptic defects associated with the kinesin-3 motor Unc-104

Zhang

Adib

et al. 2017

eLife

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The kinesin-3 family member Unc-104/KIF1A is required for axonal transport of many presynaptic components to synapses, and mutation of this gene results in synaptic dysfunction in mice, flies and worms. Our studies at the Drosophila neuromuscular junction indicate that many synaptic defects in unc-104-null mutants are mediated independently of Unc-104’s transport function, via the Wallenda (Wnd)/DLK MAP kinase axonal damage signaling pathway. Wnd signaling becomes activated when Unc-104’s function is disrupted, and leads to impairment of synaptic structure and function by restraining the expression level of active zone (AZ) and synaptic vesicle (SV) components. This action concomitantly suppresses the buildup of synaptic proteins in neuronal cell bodies, hence may play an adaptive role to stresses that impair axonal transport. Wnd signaling also becomes activated when pre-synaptic proteins are over-expressed, suggesting the existence of a feedback circuit to match synaptic protein levels to the transport capacity of the axon.

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Section: Resultssupporting

confidence: 85%

Restraint of presynaptic protein levels by Wnd/DLK signaling mediates synaptic defects associated with the kinesin-3 motor Unc-104

Zhang

Adib

et al. 2017

eLife

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“…α-Syn mediated neurotoxicity was hypothesized to be caused by α-Syn affecting transport of SV via direct interaction with the trafficking machinery (Gitler et al, 2008 ). Furthermore, studies in Drosophila melanogaster suggest that Rab3 is also involved in the formation of the AZ architecture, however the mechanisms remain unknown (Chen et al, 2015 ; Bae et al, 2016 ).…”

Section: The Janus Face Of Presynaptic α-Syn: Physiology and Pathologmentioning

confidence: 99%

Mechanisms of α-Synuclein Induced Synaptopathy in Parkinson's Disease

2018

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Parkinson's disease (PD) is characterized by intracellular inclusions of aggregated and misfolded α-Synuclein (α-Syn), and the loss of dopaminergic (DA) neurons in the brain. The resulting motor abnormalities mark the progression of PD, while non-motor symptoms can already be identified during early, prodromal stages of disease. Recent studies provide evidence that during this early prodromal phase, synaptic and axonal abnormalities occur before the degenerative loss of neuronal cell bodies. These early phenotypes can be attributed to synaptic accumulation of toxic α-Syn. Under physiological conditions, α-Syn functions in its native conformation as a soluble monomer. However, PD patient brains are characterized by intracellular inclusions of insoluble fibrils. Yet, oligomers and protofibrils of α-Syn have been identified to be the most toxic species, with their accumulation at presynaptic terminals affecting several steps of neurotransmitter release. First, high levels of α-Syn alter the size of synaptic vesicle pools and impair their trafficking. Second, α-Syn overexpression can either misregulate or redistribute proteins of the presynaptic SNARE complex. This leads to deficient tethering, docking, priming and fusion of synaptic vesicles at the active zone (AZ). Third, α-Syn inclusions are found within the presynaptic AZ, accompanied by a decrease in AZ protein levels. Furthermore, α-Syn overexpression reduces the endocytic retrieval of synaptic vesicle membranes during vesicle recycling. These presynaptic alterations mediated by accumulation of α-Syn, together impair neurotransmitter exocytosis and neuronal communication. Although α-Syn is expressed throughout the brain and enriched at presynaptic terminals, DA neurons are the most vulnerable in PD, likely because α-Syn directly regulates dopamine levels. Indeed, evidence suggests that α-Syn is a negative modulator of dopamine by inhibiting enzymes responsible for its synthesis. In addition, α-Syn is able to interact with and reduce the activity of VMAT2 and DAT. The resulting dysregulation of dopamine levels directly contributes to the formation of toxic α-Syn oligomers. Together these data suggest a vicious cycle of accumulating α-Syn and deregulated dopamine that triggers synaptic dysfunction and impaired neuronal communication, ultimately causing synaptopathy and progressive neurodegeneration in Parkinson's disease.

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“…Following core synaptic assembly, synapse maturation ensues, leading to the recruitment of additional synaptic components and formation of highly specialized pre-and post-synaptic structures that result in a several fold increase in the efficacy and strength of nascent or previously silent synapses (Rasse et al, 2005 ; Fouquet et al, 2009 ; Owald and Sigrist, 2009 ; Owald et al, 2010 ). Nucleation of the CAZ is an early step in synapse maturation (Graf et al, 2009 ; Bae et al, 2016 ). An important role has been attributed to the small GTPase Rab3 in the distribution of AZ proteins to individual release sites at the Drosophila NMJ (Graf et al, 2009 ).…”

Section: Introductionmentioning

confidence: 99%

The Drosophila KIF1A Homolog unc-104 Is Important for Site-Specific Synapse Maturation

Zhang

Hannan

Stapper

et al. 2016

Front. Cell. Neurosci.

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Mutations in the kinesin-3 family member KIF1A have been associated with hereditary spastic paraplegia (HSP), hereditary and sensory autonomic neuropathy type 2 (HSAN2) and non-syndromic intellectual disability (ID). Both autosomal recessive and autosomal dominant forms of inheritance have been reported. Loss of KIF1A or its homolog unc-104 causes early postnatal or embryonic lethality in mice and Drosophila, respectively. In this study, we use a previously described hypomorphic allele of unc-104, unc-104bris, to investigate the impact of partial loss-of-function of kinesin-3 on synapse maturation at the Drosophila neuromuscular junction (NMJ). Unc-104bris mutants exhibit structural defects where a subset of synapses at the NMJ lack all investigated active zone (AZ) proteins, suggesting a complete failure in the formation of the cytomatrix at the active zone (CAZ) at these sites. Modulating synaptic Bruchpilot (Brp) levels by ectopic overexpression or RNAi-mediated knockdown suggests that the loss of AZ components such as Ca2+ channels and Liprin-α is caused by impaired kinesin-3 based transport rather than due to the absence of the key AZ organizer protein, Brp. In addition to defects in CAZ assembly, unc-104bris mutants display further defects such as depletion of dense core and synaptic vesicle (SV) markers from the NMJ. Notably, the level of Rab3, which is important for the allocation of AZ proteins to individual release sites, was severely reduced at unc-104bris mutant NMJs. Overexpression of Rab3 partially ameliorates synaptic phenotypes of unc-104bris larvae, suggesting that lack of presynaptic Rab3 contributes to defects in synapse maturation.

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Rab3-GEF Controls Active Zone Development at theDrosophilaNeuromuscular Junction

Cited by 13 publications

References 47 publications

Restraint of presynaptic protein levels by Wnd/DLK signaling mediates synaptic defects associated with the kinesin-3 motor Unc-104

Restraint of presynaptic protein levels by Wnd/DLK signaling mediates synaptic defects associated with the kinesin-3 motor Unc-104

Mechanisms of α-Synuclein Induced Synaptopathy in Parkinson's Disease

The Drosophila KIF1A Homolog unc-104 Is Important for Site-Specific Synapse Maturation

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