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 cerebellumExpressionA defect in mitochondrial fatty acid synthesis impairs iron metabolism and causes elevated ceramide levels
Dutta D, Kanca O, Byeon S, Marcogliese P, Zuo Z, Shridharan R, Park J, Lin G, Ge M, Heimer G, Kohler J, Wheeler M, Kaipparettu B, Pandey A, Bellen H. A defect in mitochondrial fatty acid synthesis impairs iron metabolism and causes elevated ceramide levels. Nature Metabolism 2023, 5: 1595-1614. PMID: 37653044, PMCID: PMC11151872, DOI: 10.1038/s42255-023-00873-0.Peer-Reviewed Original ResearchConceptsFatty acid synthesisFe-S cluster biogenesisMitochondrial fatty acid synthesisCeramide levelsMost eukaryotic cellsElevated ceramide levelsIron metabolismCluster biogenesisEukaryotic cellsLoss of functionCellular lipidomeEnoyl coenzymeNeurodegenerative phenotypeIron homeostasisHuman-derived fibroblastsMechanistic linkAcid synthesisCeramideMECRMetabolismNeurodegenerationMtFASBiogenesisLast stepMitochondriaLithium ameliorates Niemann-Pick C1 disease phenotypes by impeding STING/SREBP2 activation
Han S, Wang Q, Song Y, Pang M, Ren C, Wang J, Guan D, Xu W, Li F, Wang F, Zhou X, Fernández-Hernando C, Zhang H, Wu D, Ye Z. Lithium ameliorates Niemann-Pick C1 disease phenotypes by impeding STING/SREBP2 activation. IScience 2023, 26: 106613. PMID: 37128603, PMCID: PMC10148154, DOI: 10.1016/j.isci.2023.106613.Peer-Reviewed Original ResearchTherapeutic optionsSTING activationPotential therapeutic optionProgressive neurodegenerative phenotypeNiemann-Pick disease type CGenetic lysosomal disorderNP-C patientsCytosolic calcium concentrationDisease type CEffects of lithiumCerebellar inflammationLithium treatmentMouse modelLithium effectsLysosomal disordersNeurodegenerative phenotypeCalcium concentrationSREBP2 activationDisease phenotypeType CMiceSREBP2 pathwayActivationDeficient fibroblastsPhenotypeExploring therapeutic strategies for infantile neuronal axonal dystrophy (INAD/PARK14)
Lin G, Tepe B, McGrane G, Tipon R, Croft G, Panwala L, Hope A, Liang A, Zuo Z, Byeon S, Wang L, Pandey A, Bellen H. Exploring therapeutic strategies for infantile neuronal axonal dystrophy (INAD/PARK14). ELife 2023, 12: e82555. PMID: 36645408, PMCID: PMC9889087, DOI: 10.7554/elife.82555.Peer-Reviewed Original ResearchConceptsPatient-derived neural progenitor cellsNeural progenitor cellsPatient-derived neuronsPediatric neurodegenerative disorderRetromer functionMitochondrial morphologyEndolysosomal pathwayMitochondrial defectsProlong lifespanNeurodegenerative phenotypeProgenitor cellsMouse modelRecessive variantsNeurodegenerative disordersGene therapy approachesPathwayInfantile neuroaxonal dystrophyHomologCellsTherapeutic strategiesAzoramidePurkinje cellsFliesPhenotypeMetabolism
2017
Clinically severe CACNA1A alleles affect synaptic function and neurodegeneration differentially
Luo X, Rosenfeld J, Yamamoto S, Harel T, Zuo Z, Hall M, Wierenga K, Pastore M, Bartholomew D, Delgado M, Rotenberg J, Lewis R, Emrick L, Bacino C, Eldomery M, Akdemir Z, Xia F, Yang Y, Lalani S, Lotze T, Lupski J, Lee B, Bellen H, Wangler M. Clinically severe CACNA1A alleles affect synaptic function and neurodegeneration differentially. PLOS Genetics 2017, 13: e1006905. PMID: 28742085, PMCID: PMC5557584, DOI: 10.1371/journal.pgen.1006905.Peer-Reviewed Original ResearchMeSH KeywordsAllelesAnimalsAnimals, Genetically ModifiedCalcium ChannelsCerebellar AtaxiaChildChild, PreschoolDrosophila melanogasterFemaleGenome-Wide Association StudyGenome, HumanHumansMaleMicroscopy, Electron, TransmissionMutation, MissenseNeurodegenerative DiseasesNeuroimagingPhenotypePoint MutationConceptsNeurodegenerative phenotypeGenomic rescue constructsS4 transmembrane segmentRescue constructTransmembrane segmentsFunction phenotypesLoss of functionMissense allelesFunction allelesWild typeGlobal developmental delayToxic gainMutant clonesDominant mutationsDevelopmental delayPoint mutationsDrosophilaFunctional impactPhenotypeQ-type voltage-dependent Ca2Early-onset developmental delayNeurological phenotypeAllelesSynaptic functionNovel variants
2008
Chapter 22 α-Synuclein, CSPα, SNAREs and Neuroprotection in vivo
Chandra S, Südhof T. Chapter 22 α-Synuclein, CSPα, SNAREs and Neuroprotection in vivo. 2008, 295-308. DOI: 10.1016/b978-0-12-374028-1.00022-1.Peer-Reviewed Original ResearchΑ-synucleinDopamine replacement therapyMouse α-synucleinPathological functionsStriatal terminalsReplacement therapyPD treatmentNormal physiological functionSynaptic connectionsPresynaptic proteinsNeurodegenerative phenotypeΑ-deletionCysteine string proteinToxic gainAmino acid changesPhysiological functionsAcid changesNeuroprotectionPathogenesisTherapyFindingsNeurodegeneration
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