TDP-43/FUS in motor neuron disease: Complexity and challenges. (October 2016)

• Record Type: Journal Article
• Authors: Guerrero, Erika N.; Wang, Haibo; Mitra, Joy; Hegde, Pavana M.; Stowell, Sara E.; Liachko, Nicole F.; Kraemer, Brian C.; Garruto, Ralph M.; Rao, K.S.; Hegde, Muralidhar L.
• Is Part Of: Progress in neurobiology. Volume 145/146(2016:Oct.)
• Page Start: 78
• Page End: 97
• Publication Date: 2016-10
• Subjects: AD Alzheimer's disease -- Ago2 Argonaute 2 -- ALS Amyotrophic lateral sclerosis -- ALS/PD amyotrophic lateral sclerosis and Parkinsonism-dementia complex -- AMPA α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid -- ATF3 activating transcription factor 3 -- ATM ataxia-telangiectasia mutated -- BAC bacterial artificial chromosome -- BMAA beta-methylamino-l-alanine -- C/EBP homologous protein 10 -- Cdk6 cyclin-dependent kinase 6 -- CLIP-seq UV-cross-linking immunoprecipitation-sequencing -- CNS central nervous system -- CTD C-terminal domain -- CTFs C-terminal fragments -- DDR DNA damage response -- DNA-PK DNA-dependent protein kinase -- DSBs doublé-strand breaks -- dsDNA double-stranded DNA -- ERG ETS-related gene -- FALS familial Amyotrophic lateral sclerosis -- FET FUS, EWS and TAF15 -- FTLD frontotemporal lobar degeneration -- FUS/TLS fused in sarcoma/translocated in liposarcoma -- G3BP RasGAP SH3-domain binding protein 1 -- gadd7 growth-arrested DNA damage-inducible gene 7 -- H3 histone 3 -- H4 histone 4 -- HDAC1 histone deacetylase 1 -- HDAC6 histone deacetylase 6 -- HIV-1 human immunodeficiency virus type 1 -- HNE 4-hydroxynonenal -- hnRNP heterogeneous nuclear ribonucleoprotein -- HR homologous recombination -- iPSC induced pluripotent stem cells -- IR ionizing radiation -- LPS lipopolysaccharides -- MALAT1 metastasis-associated lung adenocarcinoma transcript 1 -- miRNA microRNA -- NEAT1 nuclear enriched abundant transcript 1 -- NES nuclear export signal -- NHEJ non-homologous end joining -- NLS nuclear localization signal -- NMDA N-methyl-d-aspartate -- NTD N-terminal domain -- OS oxidative stress -- PARP poly(ADP-ribose polymerase) -- PD Parkinson's disease -- PLDs prion-like domains -- PRMT protein arginine transferases -- Prp prion protein promoter -- PTB polypyrimidine tract-binding -- PY-NLS proline-tyrosine nuclear localization signal -- RAN repeat associated non-ATG -- RBM45 RNA-binding motif 45 -- RGG arginine-glycince-glycine -- RNA Pol II RNA polymerase II -- ROS reactive oxygen species -- RRM RNA recognition motif -- SALS sporadic Amyotrophic lateral sclerosis -- SGs stress granules -- SOD1 superoxide dismutase 1 -- SSBs single-strand breaks -- ssDNA single-stranded DNA -- TDP-43 TAR DNA-binding protein-43 -- TIA-1 T-cell intracellular antigen 1 -- TRBP transactivation-responsive RNA binding protein -- tRNP transport ribonucleoprotein particles -- UBPY ubiquitin isopeptidase Y -- UBQLN2 ubiquilin 2 -- UPF1 upframeshift protein 1 -- UPS ubiquitin-proteasome system -- WT wild type -- ZnF zinc finger; TDP-43 -- FUS/TLS -- Amyotrophic lateral sclerosis -- RNA processing -- Genome damage/repair; Neurobiology -- Periodicals; Neurology -- Periodicals; Neurology -- Periodicals; Neurobiologie -- Périodiques; 612.8
• DOI: 10.1016/j.pneurobio.2016.09.004
• Languages: English
• ISSNs: 0301-0082

Abstract

Highlights: ALS is a group of complex motor neuron diseases involving a dozen distinct and overlapping protein inclusions. The complex neuropathology of RNA/DNA binding proteins TDP-43 and FUS, their cross-talk with other ALS subtypes is critically discussed. New avenues of research involving the role of genome damage and repair defects in FUS/TDP-43-linked ALS. Lessons learned from familial TDP-43/FUS mutations and animal models. Need for an overarching approach to unravel the fundamental mechanisms based intervention strategies. 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.