CK2α regulates the transcription of BRP in Drosophila

Wairkar, Yogesh P.; Trivedi, Deepti; Natarajan, Rajalaxmi; Barnes, Kevin M.; Dolores, Lhia Krista; Cho, Phillip

doi:10.1016/j.ydbio.2013.09.025

Cited by 5 publications

(8 citation statements)

References 111 publications

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“…Finally, to test the possibility that increased transcription of BRP may lead to accumulation of BRP in axons[26], we compared the BRP protein levels in the ventral nerve cords (VNC) between WT, Par-1 OE and Par-1 T408A flies. No significant differences were noted between the levels of BRP protein in the VNCs of these genotypes (Fig 1E).…”

Section: Resultsmentioning

confidence: 99%

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Active zone proteins are transported via distinct mechanisms regulated by Par-1 kinase

et al. 2017

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Disruption of synapses underlies a plethora of neurodevelopmental and neurodegenerative disease. Presynaptic specialization called the active zone plays a critical role in the communication with postsynaptic neuron. While the role of many proteins at the active zones in synaptic communication is relatively well studied, very little is known about how these proteins are transported to the synapses. For example, are there distinct mechanisms for the transport of active zone components or are they all transported in the same transport vesicle? Is active zone protein transport regulated? In this report we show that overexpression of Par-1/MARK kinase, a protein whose misregulation has been implicated in Autism spectrum disorders (ASDs) and neurodegenerative disorders, lead to a specific block in the transport of an active zone protein component- Bruchpilot at Drosophila neuromuscular junctions. Consistent with a block in axonal transport, we find a decrease in number of active zones and reduced neurotransmission in flies overexpressing Par-1 kinase. Interestingly, we find that Par-1 acts independently of Tau-one of the most well studied substrates of Par-1, revealing a presynaptic function for Par-1 that is independent of Tau. Thus, our study strongly suggests that there are distinct mechanisms that transport components of active zones and that they are tightly regulated.

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Section: Resultsmentioning

confidence: 99%

“…All the NMJ imaging was done at muscle 4, segment A2 –A4. Imaging and analysis of intensity of proteins within axons were done as described previously[26]. Staining intensities of various proteins within the axons and the NMJs were quantified by using MetaMorph software (Molecular Devices, Sunnyvale, CA, USA).…”

Section: Methodsmentioning

confidence: 99%

Active zone proteins are transported via distinct mechanisms regulated by Par-1 kinase

et al. 2017

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“…α-Syn WT -EGFP expressing larval nerves contained CSP blocks that co-localized with α-syn (Supplementary Figure S2C). Bruchpilot (BRP), an active zone protein (Kittel et al, 2006;Wagh et al, 2006;Wairkar et al, 2013) also co-localized with α-syn accumulations (Supplementary Figure S2C). Kinesin-1 assayed using an antibody against KLC was also present within α-syn accumulations (Supplementary Figure S2C).…”

Section: Excess α-Synuclein Causes Axonal Accumulates and Disrupts Axmentioning

confidence: 99%

“…Intriguingly, significant reductions in the intensity of CSP in larval NMJs expressing α-syn WT , α-syn LP3 , or α-syn A53T were seen compared to WT (Supplementary Figure S5B, p < 0.05). We also evaluated the level of BRP, the active zone protein that is suggested to be important for neurotransmitter release at the Drosophila synapse (Kittel et al, 2006;Wagh et al, 2006;Wairkar et al, 2013) at muscle 4 segment A2. Since Drosophila larval NMJs at muscle 4 are relatively small in size compared to muscle 6/7 NMJs, we examined the entire NMJ with a higher objective lens (60×).…”

Section: Disruption Of α-Syn-mediated Axonal Transport Causes Synaptimentioning

confidence: 99%

The Non-amyloidal Component Region of α-Synuclein Is Important for α-Synuclein Transport Within Axons

Anderson

Hirpa

Zheng

et al. 2020

Front. Cell. Neurosci.

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Proper transport of the Parkinson's disease (PD) protein, α-synuclein (α-syn), is thought to be crucial for its localization and function at the synapse. Previous work has shown that defects in long distance transport within narrow caliber axons occur early in PD, but how such defects contribute to PD is unknown. Here we test the hypothesis that the NAC region is involved in facilitating proper transport of α-syn within axons via its association with membranes. Excess α-syn or fPD mutant α-syn A53T accumulates within larval axons perturbing the transport of synaptic proteins. These α-syn expressing larvae also show synaptic morphological and larval locomotion defects, which correlate with the extent of α-syn-mediated axonal accumulations. Strikingly, deletion of the NAC region (α-syn 71−82) prevented α-syn accumulations and axonal blockages, and reduced its synaptic localization due to decreased axonal entry and axonal transport of α-syn, due to less α-syn bound to membranes. Intriguingly, co-expression α-syn 71−82 with full-length α-syn rescued α-syn accumulations and synaptic morphological defects, and decreased the ratio of the insoluble higher molecular weight (HMW)/soluble low molecular weight (LMW) α-syn, indicating that this region is perhaps important for the dimerization of α-syn on membranes. Together, our observations suggest that under physiological conditions, α-syn associates with membranes via the NAC region, and that too much α-syn perturbs axonal transport via aggregate formation, instigating synaptic and behavioral defects seen in PD.

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“…Imaging and analysis of intensity of proteins within axons was performed as described previously 57 using a Nikon C1 confocal microscope. To compare different genotypes, samples were processed simultaneously.…”

Section: Methodsmentioning

confidence: 99%

Levels of Par-1 kinase determine the localization of Bruchpilot at the Drosophila neuromuscular junction synapses

Barber

Hruska

Bush

et al. 2018

Sci Rep

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Functional synaptic networks are compromised in many neurodevelopmental and neurodegenerative diseases. While the mechanisms of axonal transport and localization of synaptic vesicles and mitochondria are relatively well studied, little is known about the mechanisms that regulate the localization of proteins that localize to active zones. Recent finding suggests that mechanisms involved in transporting proteins destined to active zones are distinct from those that transport synaptic vesicles or mitochondria. Here we report that localization of BRP-an essential active zone scaffolding protein in Drosophila, depends on the precise balance of neuronal Par-1 kinase. Disruption of Par-1 levels leads to excess accumulation of BRP in axons at the expense of BRP at active zones. Temporal analyses demonstrate that accumulation of BRP within axons precedes the loss of synaptic function and its depletion from the active zones. Mechanistically, we find that Par-1 co-localizes with BRP and is present in the same molecular complex, raising the possibility of a novel mechanism for selective localization of BRP-like active zone scaffolding proteins. Taken together, these data suggest an intriguing possibility that mislocalization of active zone proteins like BRP might be one of the earliest signs of synapse perturbation and perhaps, synaptic networks that precede many neurological disorders.

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CK2α regulates the transcription of BRP in Drosophila

Cited by 5 publications

References 111 publications

Active zone proteins are transported via distinct mechanisms regulated by Par-1 kinase

Active zone proteins are transported via distinct mechanisms regulated by Par-1 kinase

The Non-amyloidal Component Region of α-Synuclein Is Important for α-Synuclein Transport Within Axons

Levels of Par-1 kinase determine the localization of Bruchpilot at the Drosophila neuromuscular junction synapses

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