Pathological and physiological functional cross-talks ofα-synuclein and tau in the central nervous system

α-Synuclein and tau are abundant multifunctional brain proteins that are mainly expressed in the presynaptic and axonal compartments of neurons,respectively.Previous works have revealed that intracellular deposition ofα-synuclein and/or tau causes many neurodegenerative disorders,including Alzheimer’s disease and Parkinson’s disease.Despite intense investigation,the normal physiological functions and roles ofα-synuclein and tau are still unclear,owing to the fact that mice with knockout of either of these proteins do not present apparent phenotypes.Interestingly,the co-occurrence ofα-synuclein and tau aggregates was found in post-mortem brains with synucleinopathies and tauopathies,some of which share similarities in clinical manifestations.Furthermore,the direct interaction ofα-synuclein with tau is considered to promote the fibrillization of each of the proteins in vitro and in vivo.On the other hand,our recent findings have revealed thatα-synuclein and tau are cooperatively involved in brain development in a stage-dependent manner.These findings indicate strong cross-talk between the two proteins in physiology and pathology.In this review,we provide a summary of the recent findings on the functional roles ofα-synuclein and tau in the physiological conditions and pathogenesis of neurodegenerative diseases.A deep understanding of the interplay betweenα-synuclein and tau in physiological and pathological conditions might provide novel targets for clinical diagnosis and therapeutic strategies to treat neurodegenerative diseases.

NP-3 Effects of Osthole Microemulsion by Nasal Administration on the Cholinergic Pathway in AD Mice

Objectives:Fructus Cnidii is the dry ripe fruit of Cnidium monnieri(L.)Cuss.,which belongs to the umbelliferous plant.It has long been used in clinic practice and has been found to have pharmacological activity in the central nervous system.Osthole is the main active component of Fructus Cnidii.However,it shows low bioavailability,fast distribution and elimination,and low concentration in the brain when given orally.In this study,we aimed to develop a new dosage form to increase the osthole concentration in the brain and enhance its pharmacological effects in the central nervous system through reducing the dosage while improving the stability and bioavailability.Thus,microemulsion containing osthole was prepared and the effects of osthole microemulsion were examined in the mouse model of Alzheimer’s disease(AD).Methods:On the basis of pseudo-ternary phase diagram,microemulsion was prepared by using polyoxyethlated Cremophor RH40 as emulsifiers,propylene glycol as assistant emulsifiers and ethyl acetate as the oil phase.The particle size and distribution of osthole microemulsion were detected by laser particle size analyzer and transmission election microscope.The content of osthole was determined by UV spectrophotometry.The effects of osthole microemulsion by nasal administration on the learning and memory abilities in scopolamine-treated mice were assessed by Morris water maze and novel object recognition tests.The superoxide dismutase(SOD)activity,glutathione(GSH)levels and malondialdehyde(MDA)contents in the serum were examined to evaluate the oxidant stress.Choline acetyltransferase(ChAT)and acetylcholinesterase(AChE)expression in the olfactory-basal forebrain pathway were detected by immunohistochemical analysis.We also investigated the acetylcholine(ACh)levels and the histological morphology in the brain.Results:The average particle size of 1μg·μL-1 osthole microemulsion was less than 15 nm.It was characterized as spheres under the transmission electron microscopy,and the osthole was completely encapsulated in the microemulsion core.Morris water maze and novel object recognition tests showed that osthole microemulsion improved spatial and object learning and memory in scopolamine-treated mice.Moreover,osthole microemulsion restored the abnormal activity of SOD and increased the levels of MDA and GSH in the serum.Brain immunohistochemistry staining showed that osthole microemulsion up-regulated ChAT expression,while down-regulated AChE in the olfactory-basal forebrain cholinergic pathway.Additionally,the ACh levels and pathological morphology in the brain were also reversed after nasal administration with osthole microemulsion.Conclusion:The 1μg·μL-1 osthole microemulsion is an ideal dosage form with a small particle size,uniform distribution and high permeation.Osthole microemulsion ameliorated memory impairment in scopolamine-teated mice,likely via the olfactory-basal forebrain cholinergic pathway and by reducing oxidative stress.The results implicate the development of intranasal brain targeting drugs as potential treatment of certain central nervous system diseases,including disorders affecting memory such as Alzheimer’s disease.

Increased attention to snake images in cynomolgus monkeys: an eye-tracking study

Previous studies have revealed faster detection of snake images in humans and non-human primates(NHPs),suggesting automatic detection of evolutionary fear-relevant stimuli.Furthermore,human studies have indicated that general fear-relevance rather than evolutionary relevance is more effective at capturing attention.However,the issue remains unclarified in NHPs.Thus,in the present study,we explored the attentional features of laboratory-reared monkeys to evolutionary and general fear-relevant stimuli(e.g.,images of snakes,capturing gloves).Eye-tracking technology was utilized to assess attentional features as it can provide more accurate latency and variables of viewing duration and frequency compared with visual search task(VST)and response latency adopted in previous studies.In addition,those with autism spectrum disorder(ASD)show abnormal attention to threatening stimuli,including snake images.Rett syndrome(RTT)is considered a subcategory of ASD due to the display of autistic features.However,the attentional features of RTT patients or animal models to such stimuli remain unclear.Therefore,we also investigated the issue in MECP2 gene-edited RTT monkeys.The influence of different cognitive loads on attention was further explored by presenting one,two,or four images to increase stimulus complexity.The eye-tracking results revealed no significant differences between RTT and control monkeys,who all presented increased viewing(duration and frequency)of snake images but not of aversive stimuli compared with control images,thus suggesting attentional preference for evolutionary rather than general fear-relevant visual stimuli.Moreover,the preference was only revealed in visual tasks composed of two or four images,suggesting its cognitive-load dependency.

Deubiquitinase USP28 inhibits ubiquitin ligase KLHL2-mediated uridine-cytidine kinase 1 degradation and confers sensitivity to 5'-azacytidine-resistant human leukemia cells

Resistance to the chemotherapeutic drug 5'-azacytidine(5'-AZA)is a major obstacle in the treatment of patients with acute myeloid leukemia(AML).The uridine-cytidine kinase 1(UCK1)has an established role in activating 5'-AZA and its protein level is significantly downregulated in patients resistant to the drug.However,the underlying molecular mechanism for the reduced UCK1 expression remains to be elucidated.We demonstrated that the ubiquitin E3 ligase KLHL2 interacted with UCK1 and mediated its polyubiquitination at the K81 residue and degradation.We showed that deubiquitinase USP28 antagonized KLHL2-mediated polyubiquitylation of UCK1.We also provided evidence that ATM-mediated phosphorylation of USP28 resulted in its disassociation from KLHL2 and UCK1 destabilization.Conversely,UCK1 phosphorylation by 5'-AZA-activated ATM enhanced the KLHL2-UCK1 complex formation,Importantly,silencing KLHL2 or USP28 overexpression not only inhibited AML cell proliferation but also sensitized AML cells to 5'-AZA-induced apoptosis in vitro and in vivo.These results were no longer observed in USP28-deficient cells.

Recommendations for the diagnosis and treatment of paroxysmal kinesigemc dyskinesia: an expert consensus in China

Paroxysmal dyskinesias are a group of neurological diseases characterized by intermittent episodes of involuntary movements with different causes.Paroxysmal kinesigenic dyskinesia(PKD)is the most common type of paroxysmal dyskinesia and can be divided into primary and secondary types based on the etiology.Clinically,PKD is characterized by recurrent and transient attacks of involuntary movements precipitated by a sudden voluntary action.The major cause of primary PKD is genetic abnormalities,and the inheritance pattern of PKD is mainly autosomal-dominant with incomplete penetrance.The proline-rich transmembrane protein 2(PRRT2)was the first identified causative gene of PKD,accounting for the majority of PKD cases worldwide.An increasing number of studies has revealed the clinical and genetic characteristics,as well as the underlying mechanisms of PKD.By seeking the views of domestic experts,we propose an expert consensus regarding the diagnosis and treatment of PKD to help establish standardized clinical evaluation and therapies for PKD.In this consensus,we review the clinical manifestations,etiology,clinical diagnostic criteria and therapeutic recommendations for PKD,and results of genetic analyses in PKD patients performed in domestic hospitals.