Search tips
Search criteria

Results 1-7 (7)

Clipboard (0)

Select a Filter Below

Year of Publication
1.  The intellectual disability protein RAB39B selectively regulates GluA2 trafficking to determine synaptic AMPAR composition 
Nature Communications  2015;6:6504.
RAB39B is a member of the RAB family of small GTPases that controls intracellular vesicular trafficking in a compartment-specific manner. Mutations in the RAB39B gene cause intellectual disability comorbid with autism spectrum disorder and epilepsy, but the impact of RAB39B loss of function on synaptic activity is largely unexplained. Here we show that protein interacting with C-kinase 1 (PICK1) is a downstream effector of GTP-bound RAB39B and that RAB39B-PICK1 controls trafficking from the endoplasmic reticulum to the Golgi and, hence, surface expression of GluA2, a subunit of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs). The role of AMPARs in synaptic transmission varies depending on the combination of subunits (GluA1, GluA2 and GluA3) they incorporate. RAB39B downregulation in mouse hippocampal neurons skews AMPAR composition towards non GluA2-containing Ca2+-permeable forms and thereby alters synaptic activity, specifically in hippocampal neurons. We posit that the resulting alteration in synaptic function underlies cognitive dysfunction in RAB39B-related disorders.
Mutations in the RAB39B gene, which encodes a protein involved in vesicular trafficking, are associated with intellectual disability, but the impact of RAB39B loss of function on synaptic activity is not known. Here the authors show that RAB39B interacts with PICK1, and that this interaction is critical for the translocation of AMPA receptor subunits into the Golgi.
PMCID: PMC4383008  PMID: 25784538
2.  Parkin regulates kainate receptors by interacting with the GluK2 subunit 
Nature Communications  2014;5:5182.
Although loss-of-function mutations in the PARK2 gene, the gene that encodes the protein parkin, cause autosomal recessive juvenile parkinsonism, the responsible molecular mechanisms remain unclear. Evidence suggests that a loss of parkin dysregulates excitatory synapses. Here we show that parkin interacts with the kainate receptor (KAR) GluK2 subunit and regulates KAR function. Loss of parkin function in primary cultured neurons causes GluK2 protein to accumulate in the plasma membrane, potentiates KAR currents and increases KAR-dependent excitotoxicity. Expression in the mouse brain of a parkin mutant causing autosomal recessive juvenile parkinsonism results in GluK2 protein accumulation and excitotoxicity. These findings show that parkin regulates KAR function in vitro and in vivo, and suggest that KAR upregulation may have a pathogenetic role in parkin-related autosomal recessive juvenile parkinsonism.
Loss-of-function mutations in the PARK2 gene are implicated in autosomal recessive juvenile parkinsonism, but the mechanisms are unclear. Here, the authors show that these mutations cause accumulation of the kainate receptor subunit GluK2 in the plasma membrane of neurons, which facilitates neuronal death.
PMCID: PMC4218952  PMID: 25316086
3.  LRRK2 kinase activity regulates synaptic vesicle trafficking and neurotransmitter release through modulation of LRRK2 macro-molecular complex 
Mutations in Leucine-rich repeat kinase 2 gene (LRRK2) are associated with familial and sporadic Parkinson's disease (PD). LRRK2 is a complex protein that consists of multiple domains executing several functions, including GTP hydrolysis, kinase activity, and protein binding. Robust evidence suggests that LRRK2 acts at the synaptic site as a molecular hub connecting synaptic vesicles to cytoskeletal elements via a complex panel of protein-protein interactions. Here we investigated the impact of pharmacological inhibition of LRRK2 kinase activity on synaptic function. Acute treatment with LRRK2 inhibitors reduced the frequency of spontaneous currents, the rate of synaptic vesicle trafficking and the release of neurotransmitter from isolated synaptosomes. The investigation of complementary models lacking LRRK2 expression allowed us to exclude potential off-side effects of kinase inhibitors on synaptic functions. Next we studied whether kinase inhibition affects LRRK2 heterologous interactions. We found that the binding among LRRK2, presynaptic proteins and synaptic vesicles is affected by kinase inhibition. Our results suggest that LRRK2 kinase activity influences synaptic vesicle release via modulation of LRRK2 macro-molecular complex.
PMCID: PMC4034499  PMID: 24904275
LRRK2; kinase; presynaptic vesicle; synaptic activity; protein interaction
4.  TSPAN7 
Bioarchitecture  2012;2(3):95-97.
Tetraspanins regulate the signaling, trafficking and biosynthetic processing of associated proteins, and may link the extracellular domain of α-chain integrins with intracellular signaling molecules, including PI4K and PKC, both of which regulate cytoskeletal architecture. We showed that TSPAN7, a member of tetraspannin-family, promotes filopodia and dendritic spine formation in cultured hippocampal neurons, and is required for spine stability and normal synaptic transmission. TSPAN7 directly interacts with the PDZ domain of protein interacting with C kinase 1 (PICK1), and associates with AMPAR subunit GluA2 and β1-integrin. TSPAN7 regulates PICK1 and GluA2/3 association, and AMPA receptor trafficking. These findings identify TSPAN7 as a key player in the morphological and functional maturation of glutamatergic synapses.
PMCID: PMC3414387  PMID: 22880149
intellectual disability; AMPAR trafficking; synapse function/plasticity; tetrasapanins; TSPAN7; integrins; PICK1
5.  The X-Linked Intellectual Disability Protein TSPAN7 Regulates Excitatory Synapse Development and AMPAR Trafficking 
Neuron  2012;73(6):1143-1158.
Mutations in TSPAN7—a member of the tetraspanin protein superfamily—are implicated in some forms of X-linked intellectual disability. Here we show that TSPAN7 overexpression promotes the formation of filopodia and dendritic spines in cultured hippocampal neurons from embryonic rats, whereas TSPAN7 silencing reduces head size and stability of spines and AMPA receptor currents. Via its C terminus, TSPAN7 interacts with the PDZ domain of protein interacting with C kinase 1 (PICK1), to regulate PICK1 and GluR2/3 association and AMPA receptor trafficking. These findings indicate that, in hippocampal neurons, TSPAN7 regulates AMPA receptor trafficking by limiting PICK1 accessibility to AMPA receptors and suggest an additional mechanism for the functional maturation of glutamatergic synapses, whose impairment is implicated in intellectual disability.
► TSPAN7 is required for spine maturation in hippocampal neurons ► TSPAN7 knockdown impairs AMPAR currents ► TSPAN7 binds PICK1 and through this interaction regulates AMPAR trafficking
Mutations in TSPAN7 protein cause human intellectual disability. Bassani et al. now find that TSPAN7 regulates trafficking of essential receptor proteins to neuron surfaces and that absence impairs neuronal maturation in young animals, potentially underlying this intellectual disability.
PMCID: PMC3314997  PMID: 22445342
6.  The X-linked intellectual disability protein IL1RAPL1 regulates excitatory synapse formation by binding PTPδ and RhoGAP2 
Human Molecular Genetics  2011;20(24):4797-4809.
Mutations of the Interleukin-1-receptor accessory protein like 1 (IL1RAPL1) gene are associated with cognitive impairment ranging from non-syndromic X-linked mental retardation to autism. IL1RAPL1 belongs to a novel family of IL1/Toll receptors, which is localized at excitatory synapses and interacts with PSD-95. We previously showed that IL1RAPL1 regulates the synaptic localization of PSD-95 by controlling c-Jun N-terminal kinase activity and PSD-95 phosphorylation. Here, we show that the IgG-like extracellular domains of IL1RAPL1 induce excitatory pre-synapse formation by interacting with protein tyrosine phosphatase delta (PTPδ). We also found that IL1RAPL1 TIR domains interact with RhoGAP2, which is localized at the excitatory post-synaptic density. More interestingly, the IL1RAPL1/PTPδ complex recruits RhoGAP2 at excitatory synapses to induce dendritic spine formation. We also found that the IL1RAPL1 paralog, IL1RAPL2, interacts with PTPδ and induces excitatory synapse and dendritic spine formation. The interaction of the IL1RAPL1 family of proteins with PTPδ and RhoGAP2 reveals a pathophysiological mechanism of cognitive impairment associated with a novel type of trans-synaptic signaling that regulates excitatory synapse and dendritic spine formation.
PMCID: PMC3221541  PMID: 21926414
7.  Inhibition of RhoA pathway rescues the endocytosis defects in Oligophrenin1 mouse model of mental retardation 
Human Molecular Genetics  2009;18(14):2575-2583.
The patho-physiological hypothesis of mental retardation caused by the deficiency of the RhoGAP Oligophrenin1 (OPHN1), relies on the well-known functions of Rho GTPases on neuronal morphology, i.e. dendritic spine structure. Here, we describe a new function of this Bin/Amphiphysin/Rvs domain containing protein in the control of clathrin-mediated endocytosis (CME). Through interactions with Src homology 3 domain containing proteins involved in CME, OPHN1 is concentrated to endocytic sites where it down-regulates the RhoA/ROCK signaling pathway and represses the inhibitory function of ROCK on endocytosis. Indeed disruption of Ophn1 in mice reduces the endocytosis of synaptic vesicles and the post-synaptic α-amino-3-hydroxy-5-methylisoazol-4-propionate (AMPA) receptor internalization, resulting in almost a complete loss of long-term depression in the hippocampus. Finally, pharmacological inhibition of this pathway by ROCK inhibitors fully rescued not only the CME deficit in OPHN1 null cells but also synaptic plasticity in the hippocampus from Ophn1 null model. Altogether, we uncovered a new patho-physiological mechanism for intellectual disabilities associated to mutations in RhoGTPases linked genes and also opened new directions for therapeutic approaches of congenital mental retardation.
PMCID: PMC2701329  PMID: 19401298

Results 1-7 (7)