Extracellular ADP prevents neuronal apoptosis via activation of cell antioxidant enzymes and protection of mitochondrial ANT-1

Apoptosis in neuronal tissue is an efficient mechanism which contributes to both normal cell development and pathological cell death. The present study explores the effects of extracellular ADP on low [K⁺]-induced apoptosis in rat cerebellar granule cells. ADP, released into the extracellular space in brain by multiple mechanisms, can interact with its receptor or be converted, through the actions of ectoenzymes, to adenosine. The findings reported in this paper demonstrate that ADP inhibits the proapoptotic stimulus supposedly via: i) inhibition of ROS production during early stages of apoptosis, an effect mediated by its interaction with cell receptor/s. This conclusion is validated by the increase in SOD and catalase activities as well as by the GSSG/GSH ratio value decrease, in conjunction with the drop of ROS level and the prevention of the ADP protective effect by pyridoxalphosphate-6-azophenyl-2′,4′-disulfonic acid (PPADS), a novel functionally selective antagonist of purine receptor; ii) safeguard of the functionality of the mitochondrial adenine nucleotide-1 translocator (ANT-1), which is early impaired during apoptosis. This effect is mediated by its plausible internalization into cell occurring as such or after its hydrolysis, by means of plasma membrane nucleotide metabolizing enzymes, and resynthesis into the cell. Moreover, the findings that ADP also protects ANT-1 from the toxic action of the two Alzheimer's disease peptides, i.e. Aβ1–42 and NH₂htau, which are known to be produced in apoptotic cerebellar neurons, further corroborate the molecular mechanism of neuroprotection by ADP, herein proposed.     

The G protein-coupled receptor GPR162 is widely distributed in the CNS and highly expressed in the hypothalamus and in hedonic feeding areas

The Rhodopsin family is a class of integral membrane proteins belonging to G protein-coupled receptors (GPCRs). To date, several orphan GPCRs are still uncharacterized and in this study we present an anatomical characterization of the GPR162 protein and an attempt to describe its functional role. Our results show that GPR162 is widely expressed in GABAergic as well as other neurons within the mouse hippocampus, whereas extensive expression is observed in areas related to energy homeostasis and hedonic feeding such as hypothalamus, amygdala and ventral tegmental area, regions known to be involved in the regulation of palatable food consumption.     

CDR1as与疾病的相关性

环状RNA（circular RNA, circRNA）是存在于真核细胞中的一种非线性RNA,具有稳定性、特异性以及进化保守性等特征,通过发挥microRNA的海绵作用,对其靶基因进行调控。与线性RNA相比,环状RNA自身的闭合环状结构使其更具优越性。小脑变性相关蛋白1反义转录物 (cerebellar degeneration-related protein 1 antisense,CDR1as)作为一种竞争性内源RNA(competing endogenous RNA,ceRNA)间接调控miR-7靶标,通过多种途径影响多种疾病的发生和发展。本文就CDR1as的发现、来源及特征、功能以及与不同疾病的相关性作一概述。     

Depression of excitatory transmission at PF-PC synapse by group III metabotropic glutamate receptors is provided exclusively by mGluR4 in the rodent cerebellar cortex

In the rodent cerebellum, pharmacological activation of group III pre-synaptic metabotropic glutamate receptors (mGluRs) by the broad spectrum agonist l -2-amino-4-phosphonobutyric acid, acutely depresses excitatory synaptic transmission at parallel fiber (PF)-Purkinje cell (PC) synapses. Among the group III mGluR subtypes, cerebellar granule cells express predominantly mGluR4, but also mGluR7 and mGluR8 mRNA. Taking into account that previous functional and pharmacological studies have used group III mGluR broad spectrum agonists that do not differentiate between these various subtypes, their relative contribution to the modulation of glutamatergic transmission at PF-PC synapses remains to be elucidated. In order to clarify this issue, we applied conventional whole-cell patch-clamp recordings and pre-synaptic calcium influx measurements, combined with pharmacological manipulations to rat and mice cerebellar slices. With the use of (1 S ,2 R )-1-amino-2-phosphonomethylcyclopropanecarboxylic acid, a new and selective group III mGluR agonist, N -phenyl-7-(hydroxylimino)cyclopropa[b]-chromen-1a-carboxamide, the specific positive allosteric modulator of mGluR4, ( S )-3,4-dicarboxyphenylglycine, a selective mGluR8 agonist, and mGluR4 knock-out mice, we demonstrate that the inhibitory control of group III mGluRs on excitatory neurotransmission at PF-PC synapses of the rodent cerebellar cortex, is totally because of the activation of pre-synaptic mGluR4 autoreceptors.     

A peptide containing residues 26-44 of tau protein impairs mitochondrial oxidative phosphorylation acting at the level of the adenine nucleotide translocator

Having confirmed that adenovirus-mediated overexpression of NH₂-tau fragment lacking the first 25 aminoacids evokes a potent neurotoxic effect, sustained by protracted stimulation of NMDA receptors, in primary neuronal cultures we investigated whether and how chemically synthesized NH₂-derived tau peptides, i.e. NH₂-26-44 and NH₂-1-25 fragments, affect mitochondrial function. We tested both fragments on each step of the processes leading to ATP synthesis via oxidative phosphorylation: i) electron flow via the respiratory chain from physiological substrates to oxygen with the activity of each individual complex of the respiratory chain investigated in some detail, ii) membrane potential generation arising from externally added succinate and iii) the activity of both the adenine nucleotide translocator and iv) ATP synthase. Oxidative phosphorylation is not affected by NH₂-1-25 tau fragment, but dramatically impaired by NH₂-26-44 tau fragment. Both cytochrome c oxidase and the adenine nucleotide translocator are targets of NH₂-26-44 tau fragment, but adenine nucleotide translocator is the unique mitochondrial target responsible for impairment of oxidative phosphorylation by the NH₂-26-44 tau fragment, which then exerts deleterious effects on cellular availability of ATP synthesized into mitochondria.     

Roles of the Caudate Nuclei, Cerebellum, and Caudato-Cerebellar Interconnections in the Control and Coordination of Ballistic Food-Procuring Movements

We studied the roles of the cerebellum and caudate nuclei in the programming and control of ballistic movements. An experimental model of operant food-procuring movements of the rats was used; the activity of single neurons of the above structures was recorded in the course of these motor performances. To evaluate the impact of the cerebellar–caudate interaction on the process of control of the ballistic (centrally programmed) components of food-procuring motor performance, we also recorded modifications of the neuronal activity in one of the above-mentioned structures induced by electrical extrastimulation of another structure in the course of realization of the above components. It is demonstrated that the cerebellum and, in particular, its dentate nuclei are involved in the programming of ballistic food-procuring movements. Neurons of the caudate nuclei play a significant role in the immediate preparation for and subsequent current control of stereotyped ballistic movements. The high plastic properties of the cerebellar neurons manifested in the process of control of ballistic food-procuring movements are proved.