Parkin regulates kainate receptors by interacting with the GluK2 subunit

Abstract

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.

Exciting Times: New Advances Towards Understanding the Regulation and Roles of Kainate Receptors

“…Parkin ubiquitinates GluK2 in both heterologous cells and cultured neurons, and knockdown of Parkin increased GluK2 surface expression and increased vulnerability of hippocampal neurons to kainate-induced excitotoxicity. Furthermore, in a mouse model of autosomal recessive juvenile Parkinson's expressing a truncated form of Parkin, there are increased levels of GluK2 in substantia nigra and corresponding increases in cortex samples from human patients expressing mutations in Parkin [105]. Thus, GluK2 is a Parkin target that may contribute to the excitotoxic cell death of substantia nigra neurons in Parkinson's disease.…”

“…A recent study identified that the Parkinson's diseaseassociated ubiquitin ligase Parkin directly interacts with and ubiquitinates the C-terminus of GluK2 [105]. Parkin ubiquitinates GluK2 in both heterologous cells and cultured neurons, and knockdown of Parkin increased GluK2 surface expression and increased vulnerability of hippocampal neurons to kainate-induced excitotoxicity.…”

“…Thus, the current inconsistencies may reflect a complex relationship between Netos and KARs, which can be affected differential subunit expression and the availability of cell type-specific interacting proteins. Moreover, GluK2 is subject to multiple, coordinated post-translational modifications (PTMs) including phosphorylation [75], SUMOylation [67,69], ubiquitination [104,105] and palmitoylation [71,106]…”

Parkinson’s disease-linked Parkin mutations impair glutamatergic synaptic transmission and plasticity

“…Indeed, defects in glutamatergic transmission and plasticity are reported at hippocampal and corticostriatal synapses deficient in Parkin (15)(16)(17)(18)(19)(20). Parkin's mechanisms of action at excitatory synapses remain poorly understood, although its ubiquitinating activity has been found to regulate the stability and function of multiple synaptic substrates, including the presynaptic vesicle-associated protein synaptotagmins XI and IV, the postsynaptic scaffold PICK1, and the kainate receptor subunit GluK2 (21)(22)(23)(24)(25)(26). Furthermore, our recent work demonstrates that Parkin also has a structural role at the synapse, linking postsynaptic endocytic zones required for AMPA-type glutamate receptor (AMPAR) capture and internalization to the postsynaptic density through a direct interaction with the scaffold protein Homer1 (19).…”

Parkin Is Dispensable for Mitochondrial Function, but Its Ubiquitin Ligase Activity Is Critical for Macroautophagy and Neurotransmitters: Therapeutic Potential beyond Parkinson's Disease

“…Parkin overexpression reverses Aβ-induced changes in the mitochondrial TCA cycle and restores amino acid and neurotransmitter levels in AD models [68,124,129]. More recent data indicate thatexpression of a PD-linked Parkin mutant in the mouse brain causes glutamate excitotoxicity via regulation of kainate receptors [130]. High-frequency 1 H/ 13 C NMR spectroscopy shows that brain 13 C concentration is significantly increased in glutamate C4 (fig.…”