PCDH17 restricts dendritic spine morphogenesis by regulating ROCK2-dependent control of the actin cytoskeleton,modulating emotional behavior

Proper regulation of synapse formation and elimination is critical for establishing mature neuronal circuits and maintaining brain function.Synaptic abnormalities,such as defects in the density and morphology of postsynaptic dendritic spines,underlie the pathology of various neuropsychiatric disorders.Protocadherin 17(PCDH17)is associated with major mood disorders,including bipolar disorder and depression.However,the molecular mechanisms by which PCDH17 regulates spine number,morphology,and behavior remain elusive.In this study,we found that PCDH17 functions at postsynaptic sites,restricting the number and size of dendritic spines in excitatory neurons.Selective overexpression of PCDH17 in the ventral hippocampal CA1 results in spine loss and anxiety-and depression-like behaviors in mice.Mechanistically,PCDH17 interacts with actin-relevant proteins and regulates actin filament(F-actin)organization.Specifically,PCDH17 binds to ROCK2,increasing its expression and subsequently enhancing the activity of downstream targets such as LIMK1 and the phosphorylation of cofilin serine-3(Ser3).Inhibition of ROCK2 activity with belumosudil(KD025)ameliorates the defective F-actin organization and spine structure induced by PCDH17 overexpression,suggesting that ROCK2 mediates the effects of PCDH17 on F-actin content and spine development.Hence,these findings reveal a novel mechanism by which PCDH17 regulates synapse development and behavior,providing pathological insights into the neurobiological basis of mood disorders.

Celastrol enhances transcription factor EB (TFEB)-mediated autophagy and mitigates Tau pathology:Implications for Alzheimer's disease therapy

Alzheimer's disease(AD),characterized by the accumulation of protein aggregates including phosphorylated Tau aggregates,is the most common neurodegenerative disorder with limited therapeutic agents.Autophagy plays a critical role in the degradation of phosphorylated Tau aggregates,and transcription factor EB(TFEB)is a master regulator of autophagy and lysosomal biogenesis.Thus,small-molecule autophagy enhancers targeting TFEB hold promise for AD therapy.Here,we found that celastrol,an active ingredient isolated from the root extracts of Tripterygium wilfordii(Lei Gong Teng in Chinese)enhanced TFEB-mediated autophagy and lysosomal biogenesis in vitro and in mouse brains.Importantly,celastrol reduced phosphorylated Tau aggregates and attenuated memory dysfunction and cognitive deficits in P301S Tau and 3xTg mice,two commonly used AD animal models.Mechanistical studies suggest that TFEB-mediated autophagy-lysosomal pathway is responsible for phosphorylated Tau degradation in response to celastrol.Overall,our findings indicate that Celastrol is a novel TFEB activator that promotes the degradation of phosphorylated Tau aggregates and improves memory in AD animal models.Therefore,Celastrol shows potential as a novel agent for the treatment and/or prevention of AD and other tauopathies.

The relationships of vitamin D, vitamin D receptor gene polymorphisms, and vitamin D supplementation with Parkinson's disease

In recent years,many studies have investigated the correlations between Parkinson's disease(PD)and vitamin D status,but the conclusion remains elusive.The present review focuses on the associations between PD and serum vitamin D levels by reviewing studies on the associations of PD with serum vitamin D levels and vitamin D receptor(VDR)gene polymorphisms from PubMed,Web of Science,Cochrane Library,and Embase databases.We found that PD patients have lower vitamin D levels than healthy controls and that the vitamin D concentrations are negatively correlated with PD risk and severity.Furthermore,higher vitamin D concentrations are linked to better cognitive function and mood in PD patients.Findings on the relationship between VDR gene polymorphisms and the risk of PD are inconsistent,but the Fokl(C/M)polymorphism is significantly linked with PD.The occurrence of Fokl(CT)gene polymorphism may influence the risk,severity,and cognitive ability of PD patients,while also possibly influencing the effect of Vitamin D3 supplementation in PD patients.In view of the neuroprotective effects of vitamin D and the close association between vitamin D and dopaminergic neurotransmission,interventional prospective studies on vitamin D supplementation in PD patients should be conducted in the future.

Preimplantation genetic testing guidelines of International Society of Reproductive Genetics

The International Society of Reproductive Genetics(ISRG)assembled a workgroup made up of clinicians,clinical laboratory directors,and scientists for the purpose of creating the guidelines for preimplantation genetic testing(PGT).The most up-to-date information and clinical insights for the optimal PGT practice were incorporated in these guidelines.Recommendations are provided for embryologists,medical geneticists,clinical laboratorians,and other healthcare providers to improve the wellbeing of patients seeking assisted reproductive treatment and their offspring.

Contactin-associated protein-like 2(CNTNAP2)mutations impair the essentialα-secretase cleavages,leading to autism-like phenotypes

Mutations in the Contactin-associated protein-like 2(CNTNAP2)gene are associated with autism spectrum disorder(ASD),and ectodomain shedding of the CNTNAP2 protein plays a role in its function.However,key enzymes involved in the C-terminal cleavage of CNTNAP2 remain largely unknown,and the effect of ASD-associated mutations on this process and its role in ASD pathogenesis remain elusive.In this report we showed that CNTNAP2 undergoes sequential cleavages by furin,ADAM10/17-dependent a-secretase and presenilindependent y-secretase.We identified that the cleavage sites of ADAM10 and ADAM17 in CNTNAP2 locate at its C-terminal residue I79 and L96,and the main a-cleavage product C79 by ADAM10 is required for the subsequent y-secretase cleavage to generate CNTNAP2 intracellular domain(CICD).ASD-associated CNTNAP2 mutations impair the a-cleavage to generate C79,and the inhibition leads to ASDIlike repetitive and social behavior abnormalties in the Cntnap2l1254T knock-in mice.Finaly,exogenous expression of 79 improves autism-ike phenotypes in the Cntnap2^(11254T) knock-in and Cntnap2^(-/-)knockout mice.This data demonstrates that the a-secretase is essential for CNTNAP2 processing and its function.Our study indicates that inhibition of the cleavage by pathogenic mutations underlies ASD pathogenesis,and upregulation of its C-terminal fragments could have therapeutical potentials for ASD treatment.

Loss-of-function of KMT5B leads to neurodevelopmental disorder and impairs neuronal development and neurogenesis

Autism spectrum disorder(ASD)is a group of neurodevelopmental disorders that cause severe social,communication,and behavioral problems.Recent studies show that the variants of a histone methyltransferase gene KMT5B cause neurodevelopmental disorders(NDDs),including ASD,and the knockout of Kmt5b in mice is embryonic lethal.However,the detailed genotype-phenotype correlations and functional effects of KMT5B in neurodevelopment are unclear.By targeted sequencing of a large Chinese ASD cohort,analyzing published genome-wide sequencing data,and mining literature,we curated 39 KMT5B variants identified from NDD individuals.A genotype-phenotype correlation analysis for 10 individuals with KMT5B pathogenic variants reveals common symptoms,including ASD,intellectual disability,languages problem,and macrocephaly.In vitro knockdown of the expression of Kmt5b in cultured mouse primary cortical neurons leads to a decrease in neuronal dendritic complexity and an increase in dendritic spine density,which can be rescued by expression of human KMT5B but not that of pathogenic de novo missense mutants.In vivo knockdown of the Kmt5b expression in the mouse embryonic cerebral cortex by in utero electroporation results in decreased proliferation and accelerated migration of neural progenitor cells.Our findings reveal essential roles of histone methyltransferase KMT5B in neuronal development,prenatal neurogenesis,and neuronal migration.

Dysregulated CRMP Mediates Circadian Deficits in a Drosophila Model of Fragile X Syndrome

Fragile X syndrome(FXS)is the leading inherited cause of intellectual disability,resulting from the lack of functional fragile X mental retardation protein(FMRP),an mRNA binding protein mainly serving as a translational regulator.Loss of FMRP leads to dysregulation of target mRNAs.The Drosophila model of FXS show an abnormal circadian rhythm with disruption of the output pathway downstream of the clock network.Yet the FMRP targets involved in circadian regulation have not been identified.Here,we identified collapsing response mediator protein(CRMP)mRNA as a target of FMRP.Knockdown of pan-neuronal CRMP expression ameliorated the circadian defects and abnormal axonal structures of clock neurons(ventral lateral neurons)in dfmr1 mutant flies.Furthermore,specific reduction of CRMP in the downstream output insulin-producing cells attenuated the aberrant circadian behaviors.Molecular analyses revealed that FMRP binds with CRMP mRNA and negatively regulates its translation.Our results indicate that CRMP is an FMRP target and establish an essential role for CRMP in the circadian output in FXS Drosophila.

Haploinsufficiency of syncoilin leads to hypertrophic cardiomyopathy

Here we reported a SYNC nonsense variant in a Chinese family with hypertrophic cardiomyopathy(HCM)and firstly linked syncoilin(SYNC)to HCM.HCM is an inherited cardiovascular disease,affecting approximately 1:500 people,that is characterized by thickening of left ventricle(LV),especially the interventricular septum(IVS),and diastolic ventricular failure.1 To date,more than 15 genes of two groups underlying HCM have been identified.1 About 35%e60%HCM patients present autosomal dominant inheritance and carry a pathogenic variant in sarcomeric protein genes,such as b-myosin heavy chain(MYH7),myosin binding protein C(MYBPC3),and Troponin T(TNNT2).1 In addition,non-sarcomeric genetic causes of disease have also been observed in about 25%HCM patients,mainly related to metabolic storage diseases,mitochondrial cardiomyopathies,inborn errors of metabolism etc.

CNTNAP2 intracellular domain(CICD)generated byγ-secretase cleavage improves autism-related behaviors

As the most prevalent neurodevelopmental disorders in children,autism spectrum disorders(ASD)are characterized by deficits in language development,social interaction,and repetitive behaviors or inflexible interests.Contactin associated protein like 2(CNTNAP2),encoding a single transmembrane protein(CNTNAP2)with 1331 amino acid residues,is a widely validated ASD-susceptible gene.

PINK1-mediated Drp1^(S616) phosphorylation modulates synaptic development and plasticity via promoting mitochondrial fission

Dynamic change of mitochondrial morphology and distribution along neuronal branches are essential for neural circuitry formation and synaptic efficacy.However,the underlying mechanism remains elusive.We show here that Pink1 knockout(KO)mice display defective dendritic spine maturation,reduced axonal synaptic vesicles,abnormal synaptic connection,and attenuated long-term synaptic potentiation(LTP).Drp1 activation via ^(S616) phosphorylation rescues deficits of spine maturation in Pink1 KO neurons.