Phosphatidylserine improves axonal transport by inhibition of HDAC and has potential in treatment of neurodegenerative diseases

Familial dysautonomia （FD） is a rare children neurodegenerative disease caused due to a point mutation in the IKBKAP gene that results in decreased IKK complex-associated protein （IKAP） protein production. The disease affects mostly the dorsal root ganglion （DRG） and the sympathetic ganglion. Recently, we found that the molecular mechanisms underlying neurodegeneration in FD patients are defects in axonal transport of nerve growth factors and microtubule stability in the DRG. Neurons are highly polarized cells with very long axons. In order to survive and maintain proper function, neurons depend on transport of proteins and other cellular components from the neuronal body along the axons. We further demonstrated that IKAP is necessary for axon maintenance and showed that phosphatidylserine acts as an HDAC6 inhib- itor to rescue neuronal function in FD cells. In this review, we will highlight our latest research findings.

Micromorphology and Maturation of the Yellow Granules in the Hornet Gastral Cuticle

The yellow granules in the gastral cuticle of the Oriental hornet Vespa oriental＆ （Hymenoptera, Vespinae） are located in yellow stripes. In the present study, we focus on the micromorphology and formation of the yellow granules from their inception to their spread in the regions which are destined to acquire a yellow color, The cuticle was observed with several methods of electron microscopy. The results showed that the yellow granules comprise a layer which is 20-25 μm thick, within the total cuticular thickness of 40-45 μm. In the mentioned regions one can see, from above, many apertures of about 0.5μm in diameter which extends into a peripheral photoreceptor cell. In each yellow granule, one discerns a myoid envelope inside which there are 9 fibrils arranged in a circle. Yellow granules maturation process involves infiltration of canals that give rise to the incipient ball-shaped primary granules which increase in number （as a result of continues budding off the walls of a canal） as the cuticle matures and transform into secondary barrel shaped granules, becoming elongated and then splitting into shorter barrels that fill up the entire area. Preliminary examinations have suggested liver-like function activity within the layer of yellow granules.

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.

Muscle secretion of toxic factors,regulated by miR126-5p,facilitates motor neuron degeneration in amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis(ALS)is a lethal neurodegenerative disease characterized by neuromuscular junction(NMJ)disruption,motor neuron(MN)axon degeneration,and neuronal death.Unfortunately,there is currently no effective treatment available for ALS and consequently,most patients die several years post diagnosis.The neurodegeneration that occurs in ALS is considered to be a non-cell autonomous process involving interactions between the motor neuron and its diverse extracellular microenvironments via an unknown mechanism.Distal Axonopathy is one of the early disease signs;however,the involvement and contribution of neighboring tissues and specifically,the muscle environment to the disease pathology remain controversial.Few works have concluded that muscles play a minor role or none at all in ALS pathology.

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.

东方大黄蜂的表皮异源移植试验(英文)

将东方大黄蜂(胡蜂)蛹或幼蜂的棕色表皮层连同含有黑色素的皮细胞层、黄色表皮层及相连的产生黄嘌呤的皮细胞层割下,换位后植入原来的黄蜂体上(原来是黄色的部分用棕色替代,棕色的用黄色替代)。然后将蛹放回原来的子脾中,幼蜂放入一特殊的培养皿中,让其复原和发育。共对200个不同时期的蛹和50只幼蜂进行了试验。结果显示,存活的最主要是将羽化的蛹(差1-2天就羽化的蛹),早期的蛹和幼蜂均死亡。总共有约5%的蛹存活,幼蛹无一存活。在存活的蛹中,棕色表皮植入黄色区域中的不但成活了,而且还保留了棕色色彩。相反,黄色表皮在植入到棕色区域的几天后,就丢失了黄色及膜片。经过表皮异源移植的大黄蜂寿命极短,一般仅几星期。羽化后较敏感,攻击性强,但行走、飞行都很正常。

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.