FUS dysregulation disrupts synaptic homeostasis

Parkin is an E3 ligase, mutation of parkin cause autosomal recessive juvenile Parkinsonism. Here we report that parkin interacts with the kainate receptor (KAR) GluK2 subunit and regulates KAR function.

Firstly, we compared the level of GluK2 in patients, and found GluK2 subunit levels were higher in brain lysates from patients than in those from controls. And then, we wonder whether there is interaction between these two proteins. From our co-immunoprecipitated assay, we draw a conclusion that parkin interact with GluK2. And this result is further validated in brain tissues, as endogenous GluK2 co-immunoprecipitated with parkin in lysates from wild-type (wt) mouse brains.

Next, we wonder whether GluK2 is a substrate of parkin. From both sides of in vitro and in vivo, our data support that parkin can ubiquitinate GluK2.

At last, we show that loss of parkin function in primary cultured neurons causes GluK2 protein to accumulate in cell, potentiates KAR currents and increases KAR-dependent excitotoxicity.

By identifying KAR as a direct target of parkin, our results provide a step ahead towards understanding the mechanism through which parkin modulates synaptic functions. And more, patients with the PARK2 mutation might bene?t from neuroprotective therapy targeting KAR.

The RNA-binding protein fused-in-sarcoma (FUS) is associated with amyotrophic lateral sclerosis, and overexpression of wild-type FUS protein can be pathogenic in human patients. Methylation of the C-terminal RGG3 domain of FUS is necessary for transportin 1 interaction and nuclear localization. Here, we report FUS dysregulation disrupts synaptic homeostasis.

We generated transgenic mice expressing human wild-type FUS or the R521G mutation with CAG promoter. We found no detectible cytoplasmic FUS localization or protein aggregates on wild-type FUS. CAG-FUS R521G mice that escape early lethality were monitored further. They showed lower body weight. Cultured neurons from FUS-knockout mice have abnormal spine morphology as well as spine density.

Activation of metabotropic glutamate receptors 1/5 in neocortical slices and isolated synaptoneurosomes increases endogenous mouse FUS and FUSWT protein levels but decreases the FUSR521G protein. The change of FUS levels in response to mGluR activation are local synaptic events, likely related to protein synthesis. That FUS dysfunction disrupts synaptic homeostasis at dendritic spines just like another RNA-binding protein, fragile X mental retardation protein (FMRP).

In the future, we want to know disruption of synaptic homeostasis caused by dysfunction of RNA metabolism is a common theme of brain disorders or not.

To summary, this study identifies the central cleavage domain of IL-33 (amino acids 66–111) as an important functional domain of the protein and suggests that regulation with IL-33 cleavage and activation by mast cell and other inflammatory proteases could be useful to reduce IL-33–mediated responses in allergic asthma and other inflammatory diseases.

Numerologist Warda is hooked on OG-L002 fishing, collecting. And lastly her encouragement comes from socializing along with her companions.