Leon Tejwani, PhD
About
Research
Publications
2024
Lysosomal defects in Grn loss of function modulate microglial cell state and immune responses
Tejwani L, Di Paolo G. Lysosomal defects in Grn loss of function modulate microglial cell state and immune responses. Alzheimer's & Dementia 2024, 20: e090872. PMCID: PMC11710039, DOI: 10.1002/alz.090872.Peer-Reviewed Original ResearchCell statesGRN deficiencyPutative transcription factorSingle-nucleus RNA sequencingPrimary lysosomal dysfunctionMyeloid cellsEncoding progranulinGenetic perturbationsExtracellular cuesLysosomal deacidificationLysosomal healthTranscription factorsPhagocytic cargoTranscriptional remodelingSingle-nucleusLysosomal stressLysosomal degradationLysosomal propertiesLysosomal defectsGRNLysosomal functionLysosomal clearanceWild-typeLysosomal degradation processImmune response
2023
Longitudinal single-cell transcriptional dynamics throughout neurodegeneration in SCA1
Tejwani L, Ravindra N, Lee C, Cheng Y, Nguyen B, Luttik K, Ni L, Zhang S, Morrison L, Gionco J, Xiang Y, Yoon J, Ro H, Haidery F, Grijalva R, Bae E, Kim K, Martuscello R, Orr H, Zoghbi H, McLoughlin H, Ranum L, Shakkottai V, Faust P, Wang S, van Dijk D, Lim J. Longitudinal single-cell transcriptional dynamics throughout neurodegeneration in SCA1. Neuron 2023, 112: 362-383.e15. PMID: 38016472, PMCID: PMC10922326, DOI: 10.1016/j.neuron.2023.10.039.Peer-Reviewed Original ResearchReduction 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 ADifferential 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 roleActivationChapter 8 Exploring the role of protein quality control in aging and age-associated neurodegenerative diseases
Gogia N, Olmos V, Haidery F, Luttik K, Tejwani L, Lim J. Chapter 8 Exploring the role of protein quality control in aging and age-associated neurodegenerative diseases. 2022, 139-171. DOI: 10.1016/b978-0-323-90235-9.00012-4.ChaptersPQC systemAge-associated neurodegenerative diseasesAge-related neurodegenerative diseasesProtein quality control systemCell deathNeurodegenerative diseasesProtein quality controlHallmark of agingAlters cellular functionCellular proteomeCellular functionsProtein misfoldingQuality control systemCellular agingBiological processesPostmitotic natureNeuronal cell deathProteinDisease symptomsEfficient clearanceTherapeutic targetCellsDisease conditionsNervous system tissueEffective therapeutics
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 Research