Alzheimer’s disease(AD)is the most prevalent neurodegenerative disease,and the number of patients with AD is estimated to double by 2060(Alzheimer’s Association,2022).The AD mortality rate has increased by 145%over ...Alzheimer’s disease(AD)is the most prevalent neurodegenerative disease,and the number of patients with AD is estimated to double by 2060(Alzheimer’s Association,2022).The AD mortality rate has increased by 145%over the last decade,the largest increase among the ten leading causes of death in the US(Alzheimer’s Association,2022).展开更多
Background:Alzheimer's disease(AD)is the most common cause of dementia,and is characterized by amyloid-β(Aβ)plaques and tauopathy.Reducing Aβhas been considered a major AD treatment strategy in pharmacological ...Background:Alzheimer's disease(AD)is the most common cause of dementia,and is characterized by amyloid-β(Aβ)plaques and tauopathy.Reducing Aβhas been considered a major AD treatment strategy in pharmacological and non-pharmacological approaches.Impairment of gamma oscillations,which play an important role in perception and cognitive function,has been shown in mouse AD models and human patients.Recently,the therapeutic effect of gamma entrainment in AD mouse models has been reported.Given that ultrasound is an emerging neuromodulation modality,we investigated the effect of ultrasound stimulation pulsed at gamma frequency(40 Hz)in an AD mouse model.Methods:We implanted electroencephalogram(EEG)electrodes and a piezo-ceramic disc ultrasound transducer on the skull surface of 6-month-old 5×FAD and wild-type control mice(n=12 and 6,respectively).Six 5×FAD mice were treated with two-hour ultrasound stimulation at 40 Hz daily for two weeks,and the other six mice received sham treatment.Soluble and insoluble Aβlevels in the brain were measured by enzyme-linked immunosorbent assay.Spontaneous EEG gamma power was computed by wavelet analysis,and the brain connectivity was examined with phase-locking value and cross-frequency phase-amplitude coupling.Results:We found that the total Aβ42 levels,especially insoluble Aβ42;in the treatment group decreased in pre-and infra-limbic cortex(PIL)compared to that of the sham treatment group.A reduction in the number of Aβplaques was also observed in the hippocampus.There was no increase in microbleeding in the transcranial ultrasound stimulation(tUS)group.In addition,the length and number of microglial processes decreased in PIL and hippocampus.Encel-phalographic spontaneous gamma power was increased,and cross-frequency coupling was normalized,implying functional improvement after tUS stimulation.Conclusion:These results suggest that the transcranial ultrasound-based gamma-band entrainment technique can be an effective therapy for AD by reducing the Aβload and improving brain connectivity.展开更多
Prostate cancer(PCa)is the most commonly diagnosed genital cancer in men worldwide.Around 80%of the patients who developed advanced PCa suffered from bone metastasis,with a sharp drop in the survival rate.Despite grea...Prostate cancer(PCa)is the most commonly diagnosed genital cancer in men worldwide.Around 80%of the patients who developed advanced PCa suffered from bone metastasis,with a sharp drop in the survival rate.Despite great efforts,the detailed mechanisms underlying castration-resistant PCa(CRPC)remain unclear.Sirtuin 5(SIRT5),an NAD+-dependent desuccinylase,is hypothesized to be a key regulator of various cancers.However,compared to other SIRTs,the role of SIRT5 in cancer has not been extensively studied.Here,we revealed significantly decreased SIRT5 levels in aggressive PCa cells relative to the PCa stages.The correlation between the decrease in the SIRT5 level and the patient’s reduced survival rate was also confirmed.Using quantitative global succinylome analysis,we characterized a significant increase in the succinylation at lysine 118(K118su)of lactate dehydrogenase A(LDHA),which plays a role in increasing LDH activity.As a substrate of SIRT5,LDHA-K118su significantly increased the migration and invasion of PCa cells and LDH activity in PCa patients.This study reveals the reduction of SIRT5 protein expression and LDHA-K118su as a novel mechanism involved in PCa progression,which could serve as a new target to prevent CPRC progression for PCa treatment.展开更多
NEDD8 conjugation of Cullin has an important role in ubiquitin-mediated protein degradation. The COP9 signalosome, of which CSN5 is the major catalytic subunit, is a major Cullin deneddylase, Another deneddylase, Dene...NEDD8 conjugation of Cullin has an important role in ubiquitin-mediated protein degradation. The COP9 signalosome, of which CSN5 is the major catalytic subunit, is a major Cullin deneddylase, Another deneddylase, Deneddylase 1, has also been shown to process the Nedd8 precursor. In Drosophila, the DEN1 mutants do not have increased levels of Cullin neddylation, but instead show a significant decrease in neddylated Cullin. This characteristic decrease in neddylated Cullins in the DEN1^null background can be rescued by UAS-dDEN1^WT overexpression but not by overexpression of mature NEDDS, indicating that this phenotype is distinct from the NEDD8-processing function of DENI. We examined the role of DEN 1-CSN interaction in regulating Cullin neddylation. Overexpression of DEN1 in a CSN5^hypo background slightly reduced unneddylated Cullin levels. The CSN5, DEN1 double mutation partially rescues the premature lethality associated with the CSN5 single mutation. These results suggest that DEN1 regulates Cullin neddylation by suppressing CSN deneddylase activity.展开更多
基金supported by the KBRI basic research program through KBRI funded by the Ministry of Science,ICT&Future Planning(grant Nos.22-BR-02-03 and 22-BR-05-02,to HSH)the National Research Foundation of Korea(grant No.2022R1F1A1074320,to HL)。
文摘Alzheimer’s disease(AD)is the most prevalent neurodegenerative disease,and the number of patients with AD is estimated to double by 2060(Alzheimer’s Association,2022).The AD mortality rate has increased by 145%over the last decade,the largest increase among the ten leading causes of death in the US(Alzheimer’s Association,2022).
基金supported by the National Research Foundation of Korea(NRF)grant funded by the Korea government(Ministry of Science and ICT,2016M3C7A1905475 and 2018R1A2B6006797 to JGK,2017R1A5A1014708 and 2018 R1A2B6002804 to TKMinistry of Education,2015R1D1A1A01059119 to TK)+1 种基金2021 Joint Research Project of Institutes of Science and Technology to TKKBRI basic research program through Korea Brain Research Institute funded by the Ministry of Science and ICT(21-BR-03-05)to JGK.
文摘Background:Alzheimer's disease(AD)is the most common cause of dementia,and is characterized by amyloid-β(Aβ)plaques and tauopathy.Reducing Aβhas been considered a major AD treatment strategy in pharmacological and non-pharmacological approaches.Impairment of gamma oscillations,which play an important role in perception and cognitive function,has been shown in mouse AD models and human patients.Recently,the therapeutic effect of gamma entrainment in AD mouse models has been reported.Given that ultrasound is an emerging neuromodulation modality,we investigated the effect of ultrasound stimulation pulsed at gamma frequency(40 Hz)in an AD mouse model.Methods:We implanted electroencephalogram(EEG)electrodes and a piezo-ceramic disc ultrasound transducer on the skull surface of 6-month-old 5×FAD and wild-type control mice(n=12 and 6,respectively).Six 5×FAD mice were treated with two-hour ultrasound stimulation at 40 Hz daily for two weeks,and the other six mice received sham treatment.Soluble and insoluble Aβlevels in the brain were measured by enzyme-linked immunosorbent assay.Spontaneous EEG gamma power was computed by wavelet analysis,and the brain connectivity was examined with phase-locking value and cross-frequency phase-amplitude coupling.Results:We found that the total Aβ42 levels,especially insoluble Aβ42;in the treatment group decreased in pre-and infra-limbic cortex(PIL)compared to that of the sham treatment group.A reduction in the number of Aβplaques was also observed in the hippocampus.There was no increase in microbleeding in the transcranial ultrasound stimulation(tUS)group.In addition,the length and number of microglial processes decreased in PIL and hippocampus.Encel-phalographic spontaneous gamma power was increased,and cross-frequency coupling was normalized,implying functional improvement after tUS stimulation.Conclusion:These results suggest that the transcranial ultrasound-based gamma-band entrainment technique can be an effective therapy for AD by reducing the Aβload and improving brain connectivity.
基金This work was supported by the National Research Foundation of Korea and funded by the Korean Government(MSIP,Grant Nos.NRF-2018R1D1A1A02043591,2019R1H1A1079839,2020M3A9B6037812,and 2020R1A2B5B03002344)It was also supported by Korea Brain Research Institute(Grant No.21-BR-02-04).
文摘Prostate cancer(PCa)is the most commonly diagnosed genital cancer in men worldwide.Around 80%of the patients who developed advanced PCa suffered from bone metastasis,with a sharp drop in the survival rate.Despite great efforts,the detailed mechanisms underlying castration-resistant PCa(CRPC)remain unclear.Sirtuin 5(SIRT5),an NAD+-dependent desuccinylase,is hypothesized to be a key regulator of various cancers.However,compared to other SIRTs,the role of SIRT5 in cancer has not been extensively studied.Here,we revealed significantly decreased SIRT5 levels in aggressive PCa cells relative to the PCa stages.The correlation between the decrease in the SIRT5 level and the patient’s reduced survival rate was also confirmed.Using quantitative global succinylome analysis,we characterized a significant increase in the succinylation at lysine 118(K118su)of lactate dehydrogenase A(LDHA),which plays a role in increasing LDH activity.As a substrate of SIRT5,LDHA-K118su significantly increased the migration and invasion of PCa cells and LDH activity in PCa patients.This study reveals the reduction of SIRT5 protein expression and LDHA-K118su as a novel mechanism involved in PCa progression,which could serve as a new target to prevent CPRC progression for PCa treatment.
文摘NEDD8 conjugation of Cullin has an important role in ubiquitin-mediated protein degradation. The COP9 signalosome, of which CSN5 is the major catalytic subunit, is a major Cullin deneddylase, Another deneddylase, Deneddylase 1, has also been shown to process the Nedd8 precursor. In Drosophila, the DEN1 mutants do not have increased levels of Cullin neddylation, but instead show a significant decrease in neddylated Cullin. This characteristic decrease in neddylated Cullins in the DEN1^null background can be rescued by UAS-dDEN1^WT overexpression but not by overexpression of mature NEDDS, indicating that this phenotype is distinct from the NEDD8-processing function of DENI. We examined the role of DEN 1-CSN interaction in regulating Cullin neddylation. Overexpression of DEN1 in a CSN5^hypo background slightly reduced unneddylated Cullin levels. The CSN5, DEN1 double mutation partially rescues the premature lethality associated with the CSN5 single mutation. These results suggest that DEN1 regulates Cullin neddylation by suppressing CSN deneddylase activity.
