At excitatory synapses, glutamate is removed by glutamate transporters to turn off the signal. Hyaluronan is synthesized, secreted, and anchored by hyaluronan synthases at the plasma membrane. We show that hyaluronan is synthesized to support glutamate uptake by glutamate transporters. Hyaluronan synthases and glutamate transporters form a hyaluronan dependent complex, and are recruited to cellular process tips. These findings reveal that hyaluronan helps to turn off excitatory signals by supporting glutamate clearance for healthy excitatory signal tuning.

Cover Image for this issue: doi: 10.1111/jnc.14516.

Leucine-rich repeat kinase 2 (LRRK2) is a multidomain protein extensively studied being mutated in familial Parkinson's disease. Because its kinase activity is a highly promising pharmacological target for the treatment of the disease, the identification of LRRK2 substrates is crucial to understand the consequence of LRRK2 kinase inhibition. Here we demonstrated that synapsin I is phosphorylated by LRRK2 at threonine 337 and 339. Functionally, we provided several evidences that LRRK2-dependent phosphorylation of synapsin I impacts glutamate release and synaptic vesicles dynamics. Since LRRK2 mutations display increased kinase activity, our results may imply that mutant LRRK2 impair synaptic vesicle dynamics via aberrant phosphorylation of synapsinI.

Parkinson’s disease (PD) is a common degenerative disorder. Currently, no treatment strategy can slow or halt PD progression. Based on metabolomics analysis, adenosine and adenosine deaminase (ADA) were screened out as the most promising therapeutic targets for PD. Adenosine augmentation might be a rational approach to slow PD progression. Our verification study indicated for the first time that ADA inhibitor protected against dopaminergic neurodegeneration induced by the neurotoxin MPTP. Additive antiparkinsonian effects were found when ADA inhibitor was used in combination with adenosine A_2A receptors (A_2AR) antagonist. This study shed a light on the feasibility of metabolomics-driven therapeutic target identification.

Temporal lobe epilepsy (TLE) is a chronic disease that involves a disruption of blood brain barrier (BBB), linking central and peripheral systems in TLE patients, resulting in a vicious cycle, which affects the brain excitability by activation of the plasma kallikrein-kinin system. The circulation of bradykinin or related peptides in the blood or tissues, as a result of this system activation, could play a role in the interaction between central and peripheral inflammation, maintaining or even aggravating the epileptic seizure.

Open Science: This manuscript was awarded with the Open Materials Badge

For more information see: https://cos.io/our-services/open-science-badges/

Mutations in PD-associated genes such as Pink1 have been shown to contribute to dysregulation of numerous cellular processes. We identified that Pink1 endogenously interacts with a novel interacting partner FKBP5 and directly phosphorylates it. We provide evidence that Pink1 regulates AKT Ser473 phosphorylation in response to MPP⁺-induced mitochondrial stress and FKBP5 negatively regulates this phosphorylation and sensitizes cultured neurons to cell death. Our results suggest a model in which Pink1 regulates AKT through phosphorylation of FKBP5 and its interaction with AKT and PHLPP; a potential mechanism by which Pink1-FKBP5 pathway may contribute to neuronal death in PD.

Open Science: This manuscript was awarded with the Open Materials Badge

For more information see: https://cos.io/our-services/open-science-badges/

Cre/loxP recombination is a widely used approach to study gene function in vivo, using mice models expressing the Cre recombinase under the control of specific promoters or through viral delivery of Cre-expressing constructs. Our experiments show that AAV-mediated Cre recombinase expression in the substantia nigra (SN) provokes lesions of the SN pars compacta and reticulata and perturbations of dopamine-related behaviors by inducing DNA breakage, increased apoptosis, and perturbation of autophagy. These observations underscore the need for careful control of Cre toxicity when using this tool to study gene function in the brain.