Sex-Specific Microglial Responses to Glucocerebrosidase Inhibition: Relevance to GBA1-Linked Parkinson’s Disease
By onMicroglia are heterogeneous cells characterized by distinct populations, each contributing to specific biological processes in the nervous system, including neuroprotection. To elucidate the impact of sex-specific microglia heterogenicity to the susceptibility of neuronal stress, we video-recorded with time-lapse microscopy the changes in shape and motility occurring in primary cells derived from mice of both sexes in response to pro-inflammatory or neurotoxic stimulations. With this morpho-functional analysis, we documented distinct microglia subpopulations eliciting sex-specific responses to stimulation: male microglia tended to have a more pro-inflammatory phenotype, while female microglia showed increased sensitivity to conduritol-B-epoxide (CBE), a small molecule inhibitor of glucocerebrosidase, the enzyme encoded by the GBA1 gene, mutations of which are the major risk factor for Parkinson’s Disease (PD). Interestingly, glucocerebrosidase inhibition particularly impaired the ability of female microglia to enhance the Nrf2-dependent detoxification pathway in neurons, attenuating the sex differences observed in this neuroprotective function. This finding is consistent with the clinical impact of GBA1 mutations, in which the 1.5–2-fold reduced risk of developing idiopathic PD observed in female individuals is lost in the GBA1 carrier population, thus suggesting a sex-specific role for microglia in the etiopathogenesis of PD-GBA1
Local diffusion in the extracellular space of the brain
By onThe authors highlight emerging technological advances to respectively interrogate and model diffusion through the ECS, and point out how these may contribute in resolving the remaining enigmas of the ECS.
Novel green fluorescent polyamines to analyze ATP13A2 and ATP13A3 activity in the mammalian polyamine transport system
By onBiochemical evidence presented here shows that fluorescently labeled polyamines are genuine substrates of ATP13A2.
Vibrational Stabilization of Complex Network Systems
By onMany natural and man-made network systems need to maintain certain patterns, such as working at equilibria or limit cycles, to function properly. The authors provide some numerical results that demonstrate the validity of the theoretical findings.
Genetic meta-analysis of levodopa induced dyskinesia in Parkinson’s disease
By onBased on a functional annotation analysis on chromosome 1, the authors determined that changes in DNAJB4 gene expression is an additional potential cause of increased susceptibility to LiD.
Detecting rhythmic spiking through the power spectra of point process model residuals
By onThe work highlighted in this manuscript improves the ability to characterize oscillatory activity and detect pathological changes at the level of individual neurons.
Mitochondrial degradation: Mitophagy and beyond
By onMitochondria are vital for cellular function. Degradation pathways like mitophagy regulate their quality and activity. Various mechanisms, such as mitophagy and mitochondrial extrusion, ensure cellular homeostasis by removing unwanted mitochondria.
Parkinson’s genes orchestrate pyroptosis through selective trafficking of mtDNA to leaky lysosomes
By onThese data place mitochondria-to-lysosome transport as a driver of pyroptosis and link multiple PD proteins along a common inflammatory pathway.
State-dependent GABAergic regulation of striatal spiny projection neuron excitability
By onSynaptic transmission mediated by GABAA receptors (GABAARs) in adult, principal striatal spiny projection neurons (SPNs) can suppress ongoing spiking, but its effect on synaptic integration at sub-threshold membrane potentials is less well characterized, particularly those near the resting down-state. To fill this gap, a combination of molecular, optogenetic, optical and electrophysiological approaches were used to study SPNs in mouse ex vivo brain slices, and computational tools were used to model somatodendritic synaptic integration. Activation of GABAARs, either by uncaging of GABA or by optogenetic stimulation of GABAergic synapses, evoked currents with a reversal potential near −60 mV in perforated patch recordings from both juvenile and adult SPNs. Molecular profiling of SPNs suggested that this relatively positive reversal potential was not attributable to NKCC1 expression, but rather to a dynamic equilibrium between KCC2 and Cl-/HCO3- cotransporters. Regardless, from down-state potentials, optogenetic activation of dendritic GABAergic synapses depolarized SPNs. This GABAAR-mediated depolarization summed with trailing ionotropic glutamate receptor (iGluR) stimulation, promoting dendritic spikes and increasing somatic depolarization. Simulations revealed that a diffuse dendritic GABAergic input to SPNs effectively enhanced the response to coincident glutamatergic input. Taken together, our results demonstrate that GABAARs can work in concert with iGluRs to excite adult SPNs when they are in the resting down-state, suggesting that their inhibitory role is limited to brief periods near spike threshold. This state-dependence calls for a reformulation of the role intrastriatal GABAergic circuits.
Circular RNA in the human brain are tailored to neuron identity and neuropsychiatric disease
By onLittle is known about circular RNAs (circRNAs) in specific brain cells and human neuropsychiatric disease. Here, we systematically identify over 11,039 circRNAs expressed in vulnerable dopamine and pyramidal neurons laser-captured from 190 human brains and non-neuronal cells using ultra-deep, total RNA sequencing. 1526 and 3308 circRNAs are custom-tailored to the cell identity of dopamine and pyramidal neurons and enriched in synapse pathways. 29% of Parkinson's and 12% of Alzheimer's disease-associated genes produced validated circRNAs. circDNAJC6, which is transcribed from a juvenile-onset Parkinson's gene, is already dysregulated during prodromal, onset stages of common Parkinson's disease neuropathology. Globally, addiction-associated genes preferentially produce circRNAs in dopamine neurons, autism-associated genes in pyramidal neurons, and cancers in non-neuronal cells. This study shows that circular RNAs in the human brain are tailored to neuron identity and implicate circRNA-regulated synaptic specialization in neuropsychiatric diseases.
Control of mitophagy initiation and progression by the TBK1 adaptors NAP1 and SINTBAD
By onMitophagy maintains mitochondrial health by degrading damaged mitochondria. TBK1 adaptors NAP1 and SINTBAD regulate OPTN-driven mitophagy initiation and NDP52-driven progression, balancing pathway activity for efficient functioning.
Multiple genome alignment in the telomere-to-telomere assembly era
By onThis review provides an overview of the algorithmic template that most multiple genome alignment methods follow.
Structural pathway for PI3-kinase regulation by VPS15 in autophagy
By onCryo-EM analysis reveals activation pathway of PI3KC3-C1 in atomistic detail.
Biochemical consequences of glucocerebrosidase 1 mutations in Parkinson’s disease
By onPerspective on the biochemical consequences of glucocerebrosidase 1 mutations in Parkinson’s disease.
Sex Distribution of GBA1 Variants Carriers with Dementia with Lewy Bodies and Parkinson’s Disease
By onSex Distribution of GBA1 Variants Carriers with Dementia with Lewy Bodies and Parkinson's Disease
A topographical atlas of α-synuclein dosage and cell type-specific expression in adult mouse brain and peripheral organs
By onThis atlas provides much-needed insight into the cellular topography of αSyn, and provides a quantitative map to test assumptions about the role of αSyn in network vulnerability in PD and other αSynucleinopathies.
Phosphoglycerate kinase is a central leverage point in Parkinson’s disease–driven neuronal metabolic deficits
By onStudy shows increasing PGK1 gene expression enhances neuronal ATP production, protecting against synaptic dysfunction in Parkinson's disease. Boosting bioenergetics with PGK1 may be a promising therapeutic approach for PD.
iATPSnFR2: A high-dynamic-range fluorescent sensor for monitoring intracellular ATP
By onImproved iATPSnFR2 sensor offers real-time ATP level monitoring in cells. Enhanced dynamic range, high specificity, and subcellular targeting capabilities enable detailed metabolic analysis in different cellular regions.
Adaptor protein-3 produces synaptic vesicles that release phasic dopamine
By onThe burst firing of midbrain dopamine neurons releases a phasic dopamine signal that mediates reinforcement learning. At many synapses, however, high firing rates deplete synaptic vesicles (SVs), resulting in synaptic depression that limits release. What accounts for the increased release of dopamine by stimulation at high frequency? We find that adaptor protein-3 (AP-3) and its coat protein VPS41 promote axonal dopamine release by targeting vesicular monoamine transporter VMAT2 to the axon rather than dendrites. AP-3 and VPS41 also produce SVs that respond preferentially to high-frequency stimulation, independent of their role in axonal polarity. In addition, conditional inactivation of VPS41 in dopamine neurons impairs reinforcement learning, and this involves a defect in the frequency dependence of release rather than the amount of dopamine released. Thus, AP-3 and VPS41 promote the axonal polarity of dopamine release but enable learning by producing a distinct population of SVs tuned specifically to high firing frequency that confers the phasic release of dopamine.
Reduced striatal M4-cholinergic signaling following dopamine loss contributes to parkinsonian and l-DOPA–induced dyskinetic behaviors
By onImbalances in dopamine and acetylcholine affect motor function in Parkinson's disease. Contrary to conventional theories, reduced cholinergic transmission at M4 receptors in dopamine-depleted mice alleviated motor deficits and dyskinetic behavior.
