Effective extraction of polyribosomes from astrocytes enables future discoveries on translation regulation

Translation regulation is an important layer of gene expression:Generation of genome-wide expression datasets at multi-omics levels in spatial,temporal,and cell-type resolution is essential for deciphering brain complexity.Regulation of gene expression is a highly dynamic process aiming at the production of precise levels of gene products to guarantee optimal cellular function,in response to physiological cues.Speedy advances in next-generation sequencing enabled the understanding of epigenomic and transcriptomic dynamic landscapes of different brain regions along development,aging,and disease progression.However,the correlation of the“transcriptome”with protein levels is poor because numerous mRNAs are subjected to manipulation of their translation efficiency,to warrant a favorable result under certain conditions.Hence,it is widely accepted that regulation at the translation level is a vital layer of gene expression.Quantification of actively translated mRNA populations(i.e.,“translatome”)is a more reliable predictor of the“proteome”(Wang et al.,2020).

Treadmill training in Parkinson's disease:possible role of prefrontal modifications in the improved cortical-subcortical network function

Parkinson’s disease(PD)is a complex neurodegenerative disorder characterized by a range of motor symptoms such as bradykinesia,resting tremor,rigidity,and postural instability,as well as non-motor symptoms,such as depression,anxiety,sleep disturbances,and fatigue(Bloem et al.,2021).

Embracing different languages and local differences:Coconstructive patient simulation strengthens host countries’clinical training in psychiatry

BACKGROUND Global education in psychiatry is heavily influenced by knowledge from Western,high-income countries,which obscures local voices and expertise.AIM To adapt a human simulation model to psychiatric education in a context that is specific to local languages and cultures.METHODS We conducted an observational study consisting of six human simulation sessions with standardized patients from two host countries,speaking their native languages,and following an adaptation of the co-constructive patient simulation(CCPS)model.As local faculty became increasingly familiar with the CCPS approach,they took on the role of facilitators—in their country’s native language.RESULTS Fifty-three learners participated:19 child and adolescent psychiatry trainees and 3 faculty members in Türkiye(as a group that met online during 3 consecutive months);and 24 trainees and 7 faculty in Israel(divided into 3 groups,in parallel in-person sessions during a single training day).Each of the six cases reflected local realities and clinical challenges,and was associated with specific learning goals identified by each case-writing trainee.CONCLUSION Human simulation has not been fully incorporated into psychiatric education:The creation of immersive clinical experiences and the strengthening of reflective practice are two areas ripe for development.Our adaptations of CCPS can also strengthen local and regional networks and psychiatric communities of practice.Finally,the model can help question and press against hegemonies in psychiatric training that overshadow local expertise.

Mitochondrial malfunction in vanishing white matter disease： a disease of the cytosolic translation machinery

Vanishing white matter （VWM） disease - a disease of the cytosolic translation machinery： VWM is a recessive genet- ic neurodegenerative disease caused by mutations in any of the five genes encoding the subunits of translation initiation factor 2B （eIF2B） （Leegwater et al., 2001; OMIM 306896）.

Markers for neural degeneration and regeneration:novel highly sensitive methods for the measurement of thrombin and activated protein C in human cerebrospinal fluid

Inflammation and coagulation are tightly interconnected in the pathophysiology of neuronal diseases.Thrombin,a pro-coagulant serine protease is associated with neurodegeneration and its indirect inhibitor,activated protein C(aPC),is considered neuroprotective.While levels of thrombin and aPC activity are readily measured in the blood,similar assays in the cerebrospinal fluid(CSF)have not been described.The aim of this study was to establish a specific and sensitive enzymatic assay to measure both thrombin and aPC activity in the CSF.CSF was collected from 14 patients with suspected normal pressure hydrocephalus served as a control group,while seven patients with central nervous system infections served as an acute neuro-inflammatory study group and one sample of CSF following traumatic lumbar puncture served as a positive control.Thrombin and aPC activities were measured by fluorescence released by specific proteolytic cleavage in the presence of endopeptidase and amino-peptidase inhibitors to ensure specificity.Specificity of the method was verified by thrombin and serine-protease inhibitors N-alpha-((2-naphthylsulfinyl)glycyl)-DL-p-amidinophenylalanylpiperidine and phenylmethanesulfonyl fluoride.Inhibition of thrombin activity by CSF samples and levels of specific thrombin inhibitors were also assessed.Thrombin and aPC activities were reliably measured and were significantly higher in the CSF of patients with central nervous system infections compared to normal pressure hydrocephalus controls,suggesting the involvement of these factors in neuro-inflammation.CSF thrombin activity levels in the presence of known thrombin concentration were high in patients with central nervous system infections,and low in normal pressure hydrocephalus patients.Quantification of endogenous thrombin inhibitors protease nexin 1,amyloid precursor protein and anti-thrombin III in CSF by western blot indicated a significant elevation of amyloid precursor protein in infectious CSF.In conclusion,this study describes a novel and sensitive assay aimed at the detection of thrombin and aPC activity in CSF.This method may be useful for measuring these factors that reflect degenerative and protective influences of coagulation on neurological disorders.The study procedure was approved by the Ethics Committee of the Chaim Sheba Medical Center(approval No.4245-17-SMC)on October 18,2018.

Hyperbaric oxygen therapy as a new treatment approach for Alzheimer's disease

Hyperbaric oxygen therapy as a new treatment approach for Alzheimer’s disease（AD）：Alongside the increase in life expectancy,the prevalence of age-related disorders,such as neurodegenerative diseases,is on the rise.For example,AD,the most common form of dementia in the elderly,accounts for 60–80%of all dementia cases.

Postnatal therapeutic approaches in genetic neurodevelopmental disorders

Genetic neurodevelopmental disorders are characterized by abnormal neurophysiological and behavioral phenotypes,affecting individuals worldwide.While the subject has been heavily researched,current treatment options relate mostly to alleviating symptoms,rather than targeting the altered genome itself.In this review,we address the neurogenetic basis of neurodevelopmental disorders,genetic tools that are enabling precision research of these disorders in animal models,and postnatal gene-therapy approaches for neurodevelopmental disorders derived from preclinical studies in the laboratory.

Receptor-mediated increase in rabies virus axonal transport

Rabies virus （RABV） of the rhabdoviridae family is a prototype neurotropic virus that causes a fatal disease, and is still a major risk mostly in developing countries. A key step in the RABV infection process is its arrival into the central nervous system （CNS）, for which it uses the cellular transport machinery. Neurons are irregular cells with a specialized anatomy, and often extend lengthy axons that may span over a meter long. In infected organisms, RABV virions enter the neuron periphery at the area of a bite and must overcome great distances in order to reach the peripheral neuron＇s cell body and from there,

Neuromuscular junction mitochondrial enrichment: a “double-edged sword” underlying the selective motor neuron vulnerability in amyotrophic lateral sclerosis

Motor neurons are highly polarized cells,with long axons that extend to more than 1 m in the adult human.The axons further arborize into a specialized synaptic compartment,the motor unit,containing up to 2000 neuromuscular junctions(NMJs).While the size of other neuronal synapses can be up to 1μm,the NMJ is much larger and can reach 10–30μm(Jones et al.,2017).The vast size of the motor unit requires motor neurons to evolutionally adapt and supply this distal portion with a sufficient amount of ATP,as well as to replenish the axonal protein pool in order to maintain their synapses.

Dual color optogenetic control of neural populations using low-noise,multishank optoelectrodes

Optogenetics allows for optical manipulation of neuronal activity and has been increasingly combined with intracellular and extracellular electrophysiological recordings.Genetically-identified classes of neurons are optically manipulated,though the versatility of optogenetics would be increased if independent control of distinct neural populations could be achieved on a sufficient spatial and temporal resolution.We report a scalable multisite optoelectrode design that allows simultaneous optogenetic control of two spatially intermingled neuronal populations in vivo.We describe the design,fabrication,and assembly of low-noise,multisite/multicolor optoelectrodes.Each shank of the four-shank assembly is monolithically integrated with 8 recording sites and a dualcolor waveguide mixer with a 7×30μm cross-section,coupled to 405 nm and 635 nm injection laser diodes(ILDs)via gradient-index(GRIN)lenses to meet optical and thermal design requirements.To better understand noise on the recording channels generated during diode-based activation,we developed a lumped-circuit modeling approach for EMI coupling mechanisms and used it to limit artifacts to amplitudes under 100μV upto an optical output power of 450μW.We implanted the packaged devices into the CA1 pyramidal layer of awake mice,expressing Channelrhodopsin-2 in pyramidal cells and ChrimsonR in paravalbumin-expressing interneurons,and achieved optical excitation of each cell type using sub-mW illumination.We highlight the potential use of this technology for functional dissection of neural circuits.

Stepping up to meet the challenge of freezing of gait in Parkinson’s disease

There has been a growing appreciation for freezing of gait as a disabling symptom that causes a significant burden in Parkinson’s disease. Previous research has highlighted some of the key components that underlie the phenomenon, but these reductionist approaches have yet to lead to a paradigm shift resulting in the development of novel treatment strategies. Addressing this issue will require greater integration of multi-modal data with complex computational modeling, but there are a number of critical aspects that need to be considered before embarking on such an approach. This paper highlights where the field needs to address current gaps and shortcomings including the standardization of definitions and measurement, phenomenology and pathophysiology, as well as considering what available data exist and how future studies should be constructed to achieve the greatest potential to better understand and treat this devastating symptom.

Navigating the pathways:TAR-DNA-binding-protein-43 aggregation,axonal transport,and local synthesis in amyotrophic lateral sclerosis pathology

Neurons are highly polarized cells with axons reaching over a meter long in adult humans.To survive and maintain their proper function,neurons depend on specific mechanisms that regulate spatiotemporal signaling and metabolic events,which need to be carried out at the right place,time,and intensity.Such mechanisms include axonal transport,local synthesis,and liquid-liquid phase separations.Alterations and malfunctions in these processes are correlated to neurodegenerative diseases such as amyotrophic lateral sclerosis(ALS).

PARK16 locus:Differential effects of the non-coding rs823114 on Parkinson's disease risk,RNA expression,and DNA methylation

Understanding the genetic basis of Parkinson’s disease(PD)has dramatically progressed since the identification of the first genetic mutation in alpha-synuclein,to become a highly complex model of oligogenic disease(Lubbe et al.,2016;Keogh et al.,2018).

Connecting Malfunctioning Glial Cells and Brain Degenerative Disorders

The DNA damage response（DDR） is a complex biological system activated by different types of DNA damage.Mutations in certain components of the DDR machinery can lead to genomic instability disorders that culminate in tissue degeneration,premature aging,and various types of cancers.Intriguingly,malfunctioning DDR plays a role in the etiology of late onset brain degenerative disorders such as Parkinson＇s,Alzheimer＇s,and Huntington＇s diseases.For many years,brain degenerative disorders were thought to result from aberrant neural death.Here we discuss the evidence that supports our novel hypothesis that brain degenerative diseases involve dysfunction of glial cells（astrocytes,microglia,and oligodendrocytes）.Impairment in the functionality of glial cells results in pathological neuro-glial interactions that,in turn,generate a ‘‘hostile＂ environment that impairs the functionality of neuronal cells.These events can lead to systematic neural demise on a scale that appears to be proportional to the severity of the neurological deficit.

Signal-induced PARP1-Erk synergism mediates IEG expression

A recently disclosed Erk-induced PARP1 activation mediates the expression of immediate early genes(IEG)in response to a variety of extra-and intra-cellular signals implicated in memory acquisition,development and proliferation.Here,we review this mechanism,which is initiated by stimulation-induced binding of PARP1 to phosphorylated Erk translocated into the nucleus.Their binding maintains their long-lasting activity in a synergism,which offers a new pattern for targeted therapy.