2023
Reduction 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
A Novel Missense Mutation in ERCC8 Co-Segregates with Cerebellar Ataxia in a Consanguineous Pakistani Family
Gauhar Z, Tejwani L, Abdullah U, Saeed S, Shafique S, Badshah M, Choi J, Dong W, Nelson-Williams C, Lifton RP, Lim J, Raja GK. A Novel Missense Mutation in ERCC8 Co-Segregates with Cerebellar Ataxia in a Consanguineous Pakistani Family. Cells 2022, 11: 3090. PMID: 36231052, PMCID: PMC9564319, DOI: 10.3390/cells11193090.Peer-Reviewed Original ResearchConceptsAutosomal recessive cerebellar ataxiaCerebellar ataxiaProgressive gait ataxiaMagnetic resonance imagingT mutationHeterogeneous rare disordersNovel homozygous missense mutationWhole-exome sequencingMissense mutationsGait ataxiaMovement disordersDifferential diagnosisRare disorderCerebellar atrophyHomozygous missense mutationConsanguineous Pakistani familyNovel missense mutationResonance imagingBody imbalanceExome sequencingYoung adultsHomozygous mutationPakistani familyAtaxiaType A
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 variantsCortical organoids model early brain development disrupted by 16p11.2 copy number variants in autism
Urresti J, Zhang P, Moran-Losada P, Yu N, Negraes P, Trujillo C, Antaki D, Amar M, Chau K, Pramod A, Diedrich J, Tejwani L, Romero S, Sebat J, Yates III J, Muotri A, Iakoucheva L. Cortical organoids model early brain development disrupted by 16p11.2 copy number variants in autism. Molecular Psychiatry 2021, 26: 7560-7580. PMID: 34433918, PMCID: PMC8873019, DOI: 10.1038/s41380-021-01243-6.Peer-Reviewed Original ResearchConceptsCortical organoidsCommon copy number variationNeural progenitorsRatio of neuronsPotential neurobiological mechanismsOrganoid sizeEarly brain developmentSynapse numberNeuronal maturationMigration deficitsBrain developmentNeurodevelopmental processesIon channel activityNeurobiological mechanismsNeuron migrationNeocortical developmentSkin fibroblastsChannel activityPatientsEarly neurogenesisMicrocephaly phenotypeNeurite outgrowthNeuronsAutism spectrum disorderSmall GTPase RhoA
2020
Pharmacological reversal of synaptic and network pathology in human MECP2‐KO neurons and cortical organoids
Trujillo CA, Adams JW, Negraes PD, Carromeu C, Tejwani L, Acab A, Tsuda B, Thomas CA, Sodhi N, Fichter KM, Romero S, Zanella F, Sejnowski TJ, Ulrich H, Muotri AR. Pharmacological reversal of synaptic and network pathology in human MECP2‐KO neurons and cortical organoids. EMBO Molecular Medicine 2020, 13: emmm202012523. PMID: 33501759, PMCID: PMC7799367, DOI: 10.15252/emmm.202012523.Peer-Reviewed Original ResearchConceptsRett syndromeCortical organoidsPredominant etiologyNeurodevelopmental impairmentPharmacological reversalPHA-543613Neuropathologic phenotypeSynaptic dysregulationClinical studiesHuman pluripotent stem cell technologySymptomatic severityHuman neuronsMeCP2 deficiencyCandidate therapeuticsBrain mosaicismNetwork pathologyPharmacological compoundsPluripotent stem cell (iPSC) technologyNeurodevelopmental disordersMECP2 mutationsNeuropathologyMECP2 geneNeuronsCellular mosaicismStem cell technologyGenetic Risk of Autism Spectrum Disorder in a Pakistani Population
Khalid M, Raza H, Driessen T, Lee P, Tejwani L, Sami A, Nawaz M, Baig S, Lim J, Raja G. Genetic Risk of Autism Spectrum Disorder in a Pakistani Population. Genes 2020, 11: 1206. PMID: 33076578, PMCID: PMC7602870, DOI: 10.3390/genes11101206.Peer-Reviewed Original ResearchPathogenic 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 ataxias
2018
Association of CACNA1C with bipolar disorder among the Pakistani population
Khalid M, Driessen TM, Lee JS, Tejwani L, Rasool A, Saqlain M, Shiaq PA, Hanif M, Nawaz A, DeWan AT, Raja GK, Lim J. Association of CACNA1C with bipolar disorder among the Pakistani population. Gene 2018, 664: 119-126. PMID: 29684488, PMCID: PMC5970093, DOI: 10.1016/j.gene.2018.04.061.Peer-Reviewed Original ResearchConceptsBipolar disorderPakistani populationSingle nucleotide polymorphismsRisk allelesRisk score assessmentMore risk allelesScore assessmentControl individualsSignificant associationCACNA1CAssociationGenotyping resultsDisordersRs1006737Present studyNucleotide polymorphismsEthnic groupsPopulationAssociation of CACNA1CProtein-protein interaction networkRs9804190ANK3
2017
Modeling neuro-immune interactions during Zika virus infection
Mesci P, Macia A, LaRock CN, Tejwani L, Fernandes IR, Suarez NA, de A. Zanotto PM, Beltrão-Braga PCB, Nizet V, Muotri AR. Modeling neuro-immune interactions during Zika virus infection. Human Molecular Genetics 2017, 27: 41-52. PMID: 29048558, PMCID: PMC5886060, DOI: 10.1093/hmg/ddx382.Peer-Reviewed Original ResearchConceptsNeuro-immune interactionsZika virus infectionVirus infectionSerious neurologic complicationsAntiviral immune responsePro-inflammatory responseSimilar pro-inflammatory responsesNeural precursor cellsNew therapeutic drugsZIKV pathologyHepatitis CNeurologic complicationsMicroglia interactionsHuman microgliaImmune responseViral infectionBrazilian ZIKVMicrogliaInfectionNeural cellsTherapeutic drugsBirth defectsPrecursor cellsDrugsHuman tissuesModeling of TREX1-Dependent Autoimmune Disease using Human Stem Cells Highlights L1 Accumulation as a Source of Neuroinflammation
Thomas CA, Tejwani L, Trujillo CA, Negraes PD, Herai RH, Mesci P, Macia A, Crow YJ, Muotri AR. Modeling of TREX1-Dependent Autoimmune Disease using Human Stem Cells Highlights L1 Accumulation as a Source of Neuroinflammation. Cell Stem Cell 2017, 21: 319-331.e8. PMID: 28803918, PMCID: PMC5591075, DOI: 10.1016/j.stem.2017.07.009.Peer-Reviewed Original ResearchMeSH KeywordsAstrocytesAutoimmune DiseasesBase SequenceCell ExtractsChildCytosolDNAExodeoxyribonucleasesHumansInfantInfant, NewbornInflammationInterferonsLong Interspersed Nucleotide ElementsMaleMicrocephalyNervous SystemNeural Stem CellsNeuronsOrganoidsPhenotypePhosphoproteinsStem CellsUp-RegulationConceptsThree-prime repair exonuclease 1Aicardi-Goutières syndromeAutoimmune diseasesSource of neuroinflammationType I interferon secretionSystemic lupus erythematosusRepair exonuclease 1Reverse transcriptase inhibitorStem cellsDisease-relevant phenotypesNeuroinflammatory disordersLupus erythematosusTherapeutic regimensCortical organoidsInflammatory responseInterferon secretionRelated disordersObserved neurotoxicityNeural cellsNeurotoxicityDiseaseNeuronsPluripotent stem cellsDisordersHuman stem cells