Syntabulin regulates the trafficking of PICK1-containing vesicles in neurons

Xu, Junyu; Wang, Na; Luo, Jianhong; Xia, Jun

doi:10.1038/srep20924

Cited by 8 publications

(12 citation statements)

References 54 publications

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“…PICK1 knockout mice were protected against MPTP‐induced cell death . This effect of PICK1 is interesting in light of the neurotoxic and neuroinflammatory activities of PKCδ and may be another mechanism by which shifts in OMM signaling can contribute to PD pathogenesis and progression …”

Section: Omm Scaffold Proteinsmentioning

confidence: 92%

“…255 This effect of PICK1 is interesting in light of the neurotoxic and neuroinflammatory activities of PKCδ and may be another mechanism by which shifts in OMM signaling can contribute to PD pathogenesis and progression. 256 Additional scaffold proteins may also be localized to the OMM, as reports indicate that 14-3-3 may have a population of mitochondrial proteins that influence organelle signaling. 257,258 Also, the growth factor receptor-bound protein 10 (Grb10) may have OMM localization.…”

Section: Protein Interacting With C-kinase-1 (Pick1)mentioning

confidence: 99%

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Phosphoregulation on mitochondria: Integration of cell and organelle responses

2019

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Mitochondria are highly integrated organelles that are crucial to cell adaptation and mitigating adverse physiology. Recent studies demonstrate that fundamental signal transduction pathways incorporate mitochondrial substrates into their biological programs. Reversible phosphorylation is emerging as a useful mechanism to modulate mitochondrial function in accordance with cellular changes. Critical serine/threonine protein kinases, such as the c‐Jun N‐terminal kinase (JNK), protein kinase A (PKA), PTEN‐induced kinase‐1 (PINK1), and AMP‐dependent protein kinase (AMPK), readily translocate to the outer mitochondrial membrane (OMM), the interface of mitochondria‐cell communication. OMM protein kinases phosphorylate diverse mitochondrial substrates that have discrete effects on organelle dynamics, protein import, respiratory complex activity, antioxidant capacity, and apoptosis. OMM phosphorylation events can be tempered through the actions of local protein phosphatases, such as mitogen‐activated protein kinase phosphatase‐1 (MKP‐1) and protein phosphatase 2A (PP2A), to regulate the extent and duration of signaling. The central mediators of OMM signal transduction are the scaffold proteins because the relative abundance of these accessory proteins determines the magnitude and duration of a signaling event on the mitochondrial surface, which dictates the biological outcome of a local signal transduction pathway. The concentrations of scaffold proteins, such as A‐kinase anchoring proteins (AKAPs) and Sab (or SH3 binding protein 5—SH3BP5), have been shown to influence neuronal survival and vulnerability, respectively, in models of Parkinson's disease (PD), highlighting the importance of OMM signaling to health and disease. Despite recent progress, much remains to be discovered concerning the mechanisms of OMM signaling. Nonetheless, enhancing beneficial OMM signaling events and inhibiting detrimental protein‐protein interactions on the mitochondrial surface may represent highly selective approaches to restore mitochondrial health and homeostasis and mitigate organelle dysfunction in conditions such as PD.

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Section: Omm Scaffold Proteinsmentioning

confidence: 92%

Section: Protein Interacting With C-kinase-1 (Pick1)mentioning

confidence: 99%

Phosphoregulation on mitochondria: Integration of cell and organelle responses

2019

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“…As previously described (Xu et al, 2016), lentiviral pFUGW constructs, the HIV-1 packing vector Δ8.9, and VSVg envelope glycoprotein plasmid were co-transfected into HEK293T cells in a 2:1.5:1 ratio by calcium phosphate DNA co-precipitation. Fresh culture medium that replaced the transfection medium at 8 h after transfection was collected at 36 h after transfection to harvest the released viral particles.…”

Section: Methodsmentioning

confidence: 99%

Neuroligin 3 Regulates Dendritic Outgrowth by Modulating Akt/mTOR Signaling

et al. 2019

Front. Cell. Neurosci.

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Neuroligins (NLs) are a group of postsynaptic cell adhesion molecules that function in synaptogenesis and synaptic transmission. Genetic defects in neuroligin 3 (NL3), a member of the NL protein family, are associated with autism. Studies in rodents have revealed that mutations of NL3 gene lead to increased growth and complexity in dendrites in the central nervous system. However, the detailed mechanism is still unclear. In our study, we found that deficiency of NL3 led to morphological changes of the pyramidal neurons in layer II/III somatosensory cortex in mice, including enlarged somata, elongated dendritic length, and increased dendritic complexity. Knockdown of NL3 in cultured rat neurons upregulated Akt/mTOR signaling, resulting in both increased protein synthesis and dendritic growth. Treating neurons with either rapamycin to inhibit the mTOR or LY294002 to inhibit the PI3K/Akt activity rescued the morphological abnormalities resulting from either NL3 knockdown or knockout (KO). In addition, we found that the hyperactivated Akt/mTOR signaling associated with NL3 defects was mediated by a reduction in phosphatase and tensin (PTEN) expression, and that MAGI-2, a scaffold protein, interacted with both NL3 and PTEN and could be a linker between NL3 and Akt/mTOR signaling pathway. In conclusion, our results suggest that NL3 regulates neuronal morphology, especially dendritic outgrowth, by modulating the PTEN/Akt/mTOR signaling pathway, probably via MAGI-2. Thereby, this study provides a new link between NL3 and neuronal morphology.

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“…S3a – d ). STB was also reported to mediate protein interacting with C-kinase 1 (PICK1)-containing vesicular transport [ 34 ]. PICK1 plays a critical role in the surface trafficking of AMPA receptors associated with synaptic plasticity including long-term potentiation (LTP) and long-term depression (LTD) [ 35 – 37 ].…”

Section: Resultsmentioning

confidence: 99%

Defects in syntabulin-mediated synaptic cargo transport associate with autism-like synaptic dysfunction and social behavioral traits

et al. 2020

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The formation and maintenance of synapses require long-distance delivery of newly synthesized synaptic proteins from the soma to distal synapses, raising the fundamental question of whether impaired transport is associated with neurodevelopmental disorders such as autism. We previously revealed that syntabulin acts as a motor adaptor linking kinesin-1 motor and presynaptic cargos. Here, we report that defects in syntabulin-mediated transport and thus reduced formation and maturation of synapses are one of core synaptic mechanisms underlying autism-like synaptic dysfunction and social behavioral abnormalities. Syntabulin expression in the mouse brain peaks during the first two weeks of postnatal development and progressively declines during brain maturation. Neurons from conditional syntabulin −/− mice ( stb cKO) display impaired transport of presynaptic cargos, reduced synapse density and active zones, and altered synaptic transmission and long-term plasticity. Intriguingly, stb cKO mice exhibit core autism-like traits, including defective social recognition and communication, increased stereotypic behavior, and impaired spatial learning and memory. These phenotypes establish a new mechanistic link between reduced transport of synaptic cargos and impaired maintenance of synaptic transmission and plasticity, contributing to autism-associated behavioral abnormalities. This notion is further confirmed by the human missense variant STB-R178Q, which is found in an autism patient and loses its adaptor capacity for binding kinesin-1 motors. Expressing STB-R178Q fails to rescue reduced synapse formation and impaired synaptic transmission and plasticity in stb cKO neurons. Altogether, our study suggests that defects in syntabulin-mediated transport mechanisms underlie the synaptic dysfunction and behavioral abnormalities that bear similarities to autism.

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Syntabulin regulates the trafficking of PICK1-containing vesicles in neurons

Cited by 8 publications

References 54 publications

Phosphoregulation on mitochondria: Integration of cell and organelle responses

Phosphoregulation on mitochondria: Integration of cell and organelle responses

Neuroligin 3 Regulates Dendritic Outgrowth by Modulating Akt/mTOR Signaling

Defects in syntabulin-mediated synaptic cargo transport associate with autism-like synaptic dysfunction and social behavioral traits

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