2024
Ataxin-2 polyglutamine expansions aberrantly sequester TDP-43 ribonucleoprotein condensates disrupting mRNA transport and local translation in neurons
Wijegunawardana D, Nayak A, Vishal S, Venkatesh N, Gopal P. Ataxin-2 polyglutamine expansions aberrantly sequester TDP-43 ribonucleoprotein condensates disrupting mRNA transport and local translation in neurons. Developmental Cell 2024 PMID: 39419034, DOI: 10.1016/j.devcel.2024.09.023.Peer-Reviewed Original ResearchRNA-binding proteinsAtaxin-2PolyQ expansionTDP-43Like-SmLocal translationAmyotrophic lateral sclerosisDNA-binding proteinsTransactive response DNA-binding proteinLocalization of mRNAAssociated with increased riskRNA metabolismCytoskeletal mRNAsMRNA transportPolyglutamine expansionRNP condensatesMotor neuron axonsRegulatory functionsRibonucleoproteinMotor neuron integrityNeuronal integrityCortical neuronsLiquid-like propertiesNeuronal axonsMotilityRational Design of TDP-43 Derived α‑Helical Peptide Inhibitors: An In Silico Strategy to Prevent TDP-43 Aggregation in Neurodegenerative Disorders
Salaikumaran M, Gopal P. Rational Design of TDP-43 Derived α‑Helical Peptide Inhibitors: An In Silico Strategy to Prevent TDP-43 Aggregation in Neurodegenerative Disorders. ACS Chemical Neuroscience 2024, 15: 1096-1109. PMID: 38466778, PMCID: PMC10959110, DOI: 10.1021/acschemneuro.3c00659.Peer-Reviewed Original ResearchConceptsMolecular dynamics simulationsTDP-43 aggregationTDP-43Disordered C-terminal regionDynamics simulationsIntramolecular hydrogen bondsAmyloid-like filamentsPeptide inhibitorRNA/DNA-binding proteinC-terminal regionPathology of neurodegenerative diseasesNeurodegenerative diseasesAggregation of TDP-43Binding affinityStructure-based computational approachDesign of peptide inhibitorsRNA/DNA-bindingLow root-mean-square deviationRNA splicingMRNA transportPeptide-based therapeuticsRoot-mean-square deviationDevelopment of novel therapeuticsFree energy landscapeStructure predictionTDP-43 derived α-helical peptides: A novel strategy to prevent TDP-43 aggregation in neurodegenerative disorders
Salaikumaran M, Gopal P. TDP-43 derived α-helical peptides: A novel strategy to prevent TDP-43 aggregation in neurodegenerative disorders. Biophysical Journal 2024, 123: 169a. DOI: 10.1016/j.bpj.2023.11.1123.Peer-Reviewed Original Research
2022
Sequence Determinants of TDP-43 Ribonucleoprotein Condensate Formation and Axonal Transport in Neurons
Vishal SS, Wijegunawardana D, Salaikumaran MR, Gopal PP. Sequence Determinants of TDP-43 Ribonucleoprotein Condensate Formation and Axonal Transport in Neurons. Frontiers In Cell And Developmental Biology 2022, 10: 876893. PMID: 35646935, PMCID: PMC9133736, DOI: 10.3389/fcell.2022.876893.Peer-Reviewed Original ResearchAmyotrophic lateral sclerosisTDP-43A315TAxonal transportTDP-43 variantsMotor neuron degenerationTDP-43 mutationsNeuron degenerationLateral sclerosisTransport deficitsAnterograde transportNeuronsK mutationDisease-linked mutationsMotilityKey determinantPossible mechanismMutationsPrevious findingsRetrograde motilityTransport granulesAdaptor proteinSclerosisDeterminantsGranule transport
2017
Amyotrophic lateral sclerosis-linked mutations increase the viscosity of liquid-like TDP-43 RNP granules in neurons
Gopal PP, Nirschl JJ, Klinman E, Holzbaur EL. Amyotrophic lateral sclerosis-linked mutations increase the viscosity of liquid-like TDP-43 RNP granules in neurons. Proceedings Of The National Academy Of Sciences Of The United States Of America 2017, 114: e2466-e2475. PMID: 28265061, PMCID: PMC5373408, DOI: 10.1073/pnas.1614462114.Peer-Reviewed Original ResearchConceptsRNA-binding proteinRNP granulesAmyotrophic lateral sclerosis-linked mutationsCritical cellular processesRapid fluorescence recoveryAmyotrophic lateral sclerosisBiophysical propertiesDistinct biophysical propertiesRibonucleoprotein granulesSubcellular contextCellular processesSpecific RNAToxic gainTAR-DNA binding protein 43Superresolution microscopyFluorescence recoveryLiquid-liquid phase separationMutant TDP-43Primary cortical neuronsLiquid-like propertiesTDP-43RNAProteinMutationsAxonal location