2023
Dysregulation of alternative splicing in spinocerebellar ataxia type 1
Olmos V, Thompson E, Gogia N, Luttik K, Veeranki V, Ni L, Sim S, Chen K, Krause D, Lim J. Dysregulation of alternative splicing in spinocerebellar ataxia type 1. Human Molecular Genetics 2023, 33: 138-149. PMID: 37802886, PMCID: PMC10979408, DOI: 10.1093/hmg/ddad170.Peer-Reviewed Original ResearchConceptsAlternative splicing eventsSpinocerebellar ataxia type 1Splicing eventsAtaxin-1Ataxia type 1Mutant ataxin-1Alternative splicingGene expressionMisregulated alternative splicingCell-autonomous mannerDifferential gene expressionNew biological pathwaysMolecular mechanistic insightsDrosophila modelGenetic manipulationBulk RNABiological pathwaysPolyglutamine tractNeurodegenerative phenotypeAutonomous mannerMechanistic insightsSplicingPotential therapeutic strategyMouse cerebellumExpressionReduction of Nemo-like kinase increases lysosome biogenesis and ameliorates TDP-43-related neurodegeneration
Tejwani L, Jung Y, Kokubu H, Sowmithra S, Ni L, Lee C, Sanders B, Lee P, Xiang Y, Luttik K, Soriano A, Yoon J, Park J, Ro H, Ju H, Liao C, Tieze S, Rigo F, Jafar-Nejad P, Lim J. Reduction of Nemo-like kinase increases lysosome biogenesis and ameliorates TDP-43-related neurodegeneration. Journal Of Clinical Investigation 2023, 133: e138207. PMID: 37384409, PMCID: PMC10425213, DOI: 10.1172/jci138207.Peer-Reviewed Original ResearchConceptsAmyotrophic lateral sclerosisTDP-43-related neurodegenerationNeurodegenerative disordersTransactive response DNA-binding protein 43Sporadic amyotrophic lateral sclerosisDNA-binding protein 43Subset of patientsTDP-43 speciesTDP-43 inclusionsDistinct mouse modelsTDP-43 proteinopathyFamilial amyotrophic lateral sclerosisNemo-like kinaseMultiple neurodegenerative disordersAutophagy/lysosome pathwayTDP-43-positive aggregatesALS patientsALS casesSporadic ALSPharmacological reductionProtein 43Lateral sclerosisMouse modelParkinson's diseaseTDP-43
2022
Identifying Disease Signatures in the Spinocerebellar Ataxia Type 1 Mouse Cortex
Luttik K, Olmos V, Owens A, Khan A, Yun J, Driessen T, Lim J. Identifying Disease Signatures in the Spinocerebellar Ataxia Type 1 Mouse Cortex. Cells 2022, 11: 2632. PMID: 36078042, PMCID: PMC9454518, DOI: 10.3390/cells11172632.Peer-Reviewed Original ResearchConceptsSCA1 mouse modelSpinocerebellar ataxia type 1Brain regionsMotor cortexMouse modelPurkinje cellsUnique gene expression changesCranial nerve nucleiBroad brain regionsSpecific neuronal populationsCerebellar Purkinje cellsInferior olive nucleusRegion-specific mechanismsCortical pathologyAtaxin-1Synaptic dysfunctionNerve nucleiSpinocerebellar tractSpinal cordProgressive degenerationTranscriptomic changesNeuronal populationsMouse cortexMutant ataxin-1Type 1Differential effects of Wnt-β-catenin signaling in Purkinje cells and Bergmann glia in spinocerebellar ataxia type 1
Luttik K, Tejwani L, Ju H, Driessen T, Smeets CJLM, Edamakanti CR, Khan A, Yun J, Opal P, Lim J. Differential effects of Wnt-β-catenin signaling in Purkinje cells and Bergmann glia in spinocerebellar ataxia type 1. Proceedings Of The National Academy Of Sciences Of The United States Of America 2022, 119: e2208513119. PMID: 35969780, PMCID: PMC9407543, DOI: 10.1073/pnas.2208513119.Peer-Reviewed Original ResearchConceptsWnt-β-cateninSpinocerebellar ataxia type 1Ataxia type 1Cell typesWnt-β-catenin signalingWnt-β-catenin pathwayDifferent cell typesMultiple cell typesSCA1 mouse modelCerebellar cell populationsAtaxin-1Genetic manipulationCerebellar patterningBergmann gliaSCA1 pathogenesisSpecific neuronal populationsPurkinje cellsCerebellar neurodegenerationDistinct responsesCell populationsPathwayNeurodegenerative diseasesMouse cerebellumCritical roleActivationThe extra-cerebellar effects of spinocerebellar ataxia type 1 (SCA1): looking beyond the cerebellum
Olmos V, Gogia N, Luttik K, Haidery F, Lim J. The extra-cerebellar effects of spinocerebellar ataxia type 1 (SCA1): looking beyond the cerebellum. Cellular And Molecular Life Sciences 2022, 79: 404. PMID: 35802260, PMCID: PMC9993484, DOI: 10.1007/s00018-022-04419-7.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsConceptsSpinocerebellar ataxia type 1Type 1Ataxia type 1Cerebellar Purkinje cell lossProgressive motor deficitsSCA1 patientsPurkinje cell lossMouse model studiesMotor deficitsLimb incoordinationNumber of CAGMouse modelRespiratory problemsMemory impairmentCell lossCerebellar regionsCognitive defectsNeurodegenerative diseasesPatientsAtaxin-1 proteinDiverse pathologiesATXN1 expressionCerebellumDiseaseFurther investigation
2021
Microglia regulate brain Progranulin levels through the endocytosis-lysosomal pathway
Dong T, Tejwani L, Jung Y, Kokubu H, Luttik K, Driessen TM, Lim J. Microglia regulate brain Progranulin levels through the endocytosis-lysosomal pathway. JCI Insight 2021, 6: e136147. PMID: 34618685, PMCID: PMC8663778, DOI: 10.1172/jci.insight.136147.Peer-Reviewed Original ResearchConceptsPGRN levelsNovel potential therapeutic targetFrontotemporal lobar degenerationPotential therapeutic targetNeuronal ceroid lipofuscinosisPGRN deficiencyPGRN expressionLysosomal pathwayProgranulin levelsPathological changesHaploinsufficient miceTherapeutic targetMicrogliaNeuropathological phenotypeAlzheimer's diseaseProgranulinCeroid lipofuscinosisGlycoprotein progranulinNeurodegenerative diseasesDiseaseMiceGenetic alterationsNemo-like kinaseGenetic interaction studiesGenetic variants
2020
Pathogenic mechanisms underlying spinocerebellar ataxia type 1
Tejwani L, Lim J. Pathogenic mechanisms underlying spinocerebellar ataxia type 1. Cellular And Molecular Life Sciences 2020, 77: 4015-4029. PMID: 32306062, PMCID: PMC7541529, DOI: 10.1007/s00018-020-03520-z.Peer-Reviewed Original ResearchConceptsGait impairmentSpinocerebellar ataxiaHeterogenous clinical manifestationsProgressive gait impairmentAdditional clinical featuresIon channel dysfunctionKey cellular changesCommon gait impairmentNervous system biologyHereditary cerebellar ataxiaClinical featuresClinical manifestationsCerebellar featuresCerebellar atrophyAutosomal dominant spinocerebellar ataxiaChannel dysfunctionPathogenic mechanismsDisease pathogenesisMolecular pathogenesisCerebellar ataxiaType 1Spinocerebellar ataxia type 1Central mechanismsAtaxia type 1Dominant spinocerebellar ataxiasNemo-like kinase reduces mutant huntingtin levels and mitigates Huntington’s disease
Jiang M, Zhang X, Liu H, LeBron J, Alexandris A, Peng Q, Gu H, Yang F, Li Y, Wang R, Hou Z, Arbez N, Ren Q, Dong JL, Whela E, Wang R, Ratovitski T, Troncoso JC, Mori S, Ross CA, Lim J, Duan W. Nemo-like kinase reduces mutant huntingtin levels and mitigates Huntington’s disease. Human Molecular Genetics 2020, 29: 1340-1352. PMID: 32242231, PMCID: PMC7254850, DOI: 10.1093/hmg/ddaa061.Peer-Reviewed Original ResearchConceptsBrain atrophyHD miceNemo-like kinaseMHTT levelsHD mouse modelsNew molecular targetsHD human brainHuntingtin proteinEffect of NLKMouse striatal cellsFurther mechanistic studiesActivity-dependent mannerHTT protein levelsMouse modelAdult brainStriatal cellsProtective roleMutant Htt aggregationAmino acids 120Huntington's diseaseMutant huntingtin levelsMolecular targetsHuntingtin levelsProtein levelsBrain
2018
Molecular pathway analysis towards understanding tissue vulnerability in spinocerebellar ataxia type 1
Driessen TM, Lee PJ, Lim J. Molecular pathway analysis towards understanding tissue vulnerability in spinocerebellar ataxia type 1. ELife 2018, 7: e39981. PMID: 30507379, PMCID: PMC6292693, DOI: 10.7554/elife.39981.Peer-Reviewed Original ResearchConceptsSpinocerebellar ataxia type 1Ataxia type 1Biological pathwaysGene expression changesMolecular pathway analysisSCA1 mouse modelExpression changesPathway analysisMouse modelDisease initiationInferior oliveMolecular alterationsPathwayAffected tissuesSpecific differencesVulnerable tissuesTissue vulnerabilityType 1Different mechanismsGenesTissueOliveFirst time
2015
Nemo-like kinase is a novel regulator of spinal and bulbar muscular atrophy
Todd TW, Kokubu H, Miranda HC, Cortes CJ, La Spada AR, Lim J. Nemo-like kinase is a novel regulator of spinal and bulbar muscular atrophy. ELife 2015, 4: e08493. PMID: 26308581, PMCID: PMC4577982, DOI: 10.7554/elife.08493.Peer-Reviewed Original ResearchConceptsNemo-like kinaseMuscular atrophyExact pathogenic mechanismProgressive neuromuscular diseaseAndrogen receptor proteinSBMA phenotypePathogenic mechanismsDisease pathogenesisNeuromuscular diseaseGene transcriptionTherapy developmentAtrophySBMAAR fragmentReceptor proteinPolyglutamine expansionMolecular mechanismsNovel regulatorNovel avenuesToxicityPathogenesisDiseaseMice
2013
Polyglutamine Disease Toxicity Is Regulated by Nemo-like Kinase in Spinocerebellar Ataxia Type 1
Ju H, Kokubu H, Todd TW, Kahle JJ, Kim S, Richman R, Chirala K, Orr HT, Zoghbi HY, Lim J. Polyglutamine Disease Toxicity Is Regulated by Nemo-like Kinase in Spinocerebellar Ataxia Type 1. Journal Of Neuroscience 2013, 33: 9328-9336. PMID: 23719801, PMCID: PMC3710458, DOI: 10.1523/jneurosci.3465-12.2013.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAnimals, Genetically ModifiedAtaxin-1AtaxinsBehavior, AnimalBlotting, WesternBrainCerebellumChromatography, GelDrosophila melanogasterFemaleGene ExpressionHEK293 CellsHeredodegenerative Disorders, Nervous SystemHumansImmunoprecipitationMiceMice, Inbred C57BLMice, TransgenicMitogen-Activated Protein KinasesNerve Tissue ProteinsNuclear ProteinsPeptidesPhosphorylationProtein Serine-Threonine KinasesSpinocerebellar Ataxias