Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
5739135 | Progress in Neurobiology | 2016 | 61 Pages |
Abstract
Amyotrophic lateral sclerosis (ALS), a common motor neuron disease affecting two per 100,000 people worldwide, encompasses at least five distinct pathological subtypes, including, ALS-SOD1, ALS-C9orf72, ALS-TDP-43, ALS-FUS and Guam-ALS. The etiology of a major subset of ALS involves toxicity of the TAR DNA-binding protein-43 (TDP-43). A second RNA/DNA binding protein, fused in sarcoma/translocated in liposarcoma (FUS/TLS) has been subsequently associated with about 1% of ALS patients. While mutations in TDP-43 and FUS have been linked to ALS, the key contributing molecular mechanism(s) leading to cell death are still unclear. One unique feature of TDP-43 and FUS pathogenesis in ALS is their nuclear clearance and simultaneous cytoplasmic aggregation in affected motor neurons. Since the discoveries in the last decade implicating TDP-43 and FUS toxicity in ALS, a majority of studies have focused on their cytoplasmic aggregation and disruption of their RNA-binding functions. However, TDP-43 and FUS also bind to DNA, although the significance of their DNA binding in disease-affected neurons has been less investigated. A recent observation of accumulated genomic damage in TDP-43 and FUS-linked ALS and association of FUS with neuronal DNA damage repair pathways indicate a possible role of deregulated DNA binding function of TDP-43 and FUS in ALS. In this review, we discuss the different ALS disease subtypes, crosstalk of etiopathologies in disease progression, available animal models and their limitations, and recent advances in understanding the specific involvement of RNA/DNA binding proteins, TDP-43 and FUS, in motor neuron diseases.
Keywords
nESLPS4-hydroxynonenaldsDNADDRERGNHEJCTDSGSBMAAAMPAFETNMDAN-methyl-d-aspartateDSBsIPSCPrPSOD1FTLDHNEATF3TDP-43PARPNLSTIA-1hnRNPTAR DNA-binding protein-43HDAC1NTDPRMTPTBssDNAHDAC6SALSDNA-PKCLIP-seqZNFG3BPNEAT1Nuclear enriched abundant transcript 1UPF1RRMTRBPETS-related genePY-NLSUBQLN2fused in sarcoma/translocated in liposarcomaubiquilin 2CTFSRGGC-terminal fragmentstrnPRNA polymerase IIataxia-telangiectasia mutatedC/EBPCdk6Single-stranded DNAdouble-stranded DNAFUS/TLSBACRNA recognition motifRNA pol IIROSSSBsArgonaute 2amyotrophic lateral sclerosisSporadic amyotrophic lateral sclerosisfamilial amyotrophic lateral sclerosisα-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acidZinc fingerAgo2Alzheimer’s diseaseALSParkinson’s diseaseionizing radiationOxidative stressfALSATMC-terminal domainN-terminal domainCNSfrontotemporal lobar degenerationMetastasis-associated lung adenocarcinoma transcript 1heterogeneous nuclear ribonucleoproteinInduced pluripotent stem cellssuperoxide dismutase 1Ubiquitin-proteasome systemcentral nervous systemcyclin-dependent kinase 6nuclear export signalnuclear localization signalRånsingle-strand breaksdouble-strand breaksnon-homologous end joiningactivating transcription factor 3LipopolysaccharidesMALAT1MicroRNAMiRNAHomologous recombinationwild typeHistone 3histone 4histone deacetylase 1Histone deacetylase 6DNA-dependent protein kinaseDNA damage responseHIV-1Human immunodeficiency virus type 1RNA processingbacterial artificial chromosomeStress granulesReactive oxygen speciesUPS
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Authors
Erika N. Guerrero, Haibo Wang, Joy Mitra, Pavana M. Hegde, Sara E. Stowell, Nicole F. Liachko, Brian C. Kraemer, Ralph M. Garruto, K.S. Rao, Muralidhar L. Hegde,