Pathological hallmarks of amyotrophic lateral sclerosis/frontotemporal lobar degeneration in transgenic mice produced with TDP-43 genomic fragments.

Transactive response DNA-binding protein 43 ubiquitinated inclusions are a hallmark of amyotrophic lateral sclerosis and of frontotemporal lobar degeneration with ubiquitin-positive inclusions. Yet, mutations in TARDBP, the gene encoding these inclusions are associated with only 3% of sporadic and familial amyotrophic lateral sclerosis. Recent transgenic mouse studies have revealed a high degree of toxicity due to transactive response DNA-binding protein 43 proteins when overexpressed under the control of strong neuronal gene promoters, resulting in early paralysis and death, but without the presence of amyotrophic lateral sclerosis-like ubiquitinated transactive response DNA-binding protein 43-positive inclusions. To better mimic human amyotrophic lateral sclerosis, we generated transgenic mice that exhibit moderate and ubiquitous expression of transactive response DNA-binding protein 43 species using genomic fragments that encode wild-type human transactive response DNA-binding protein 43 or familial amyotrophic lateral sclerosis-linked mutant transactive response DNA-binding protein 43 (G348C) and (A315T). These novel transgenic mice develop many age-related pathological and biochemical changes reminiscent of human amyotrophic lateral sclerosis including ubiquitinated transactive response DNA-binding protein 43-positive inclusions, transactive response DNA-binding protein 43 cleavage fragments, intermediate filament abnormalities, axonopathy and neuroinflammation. All three transgenic mouse models (wild-type, G348C and A315T) exhibited impaired learning and memory capabilities during ageing, as well as motor dysfunction. Real-time imaging with the use of biophotonic transactive response DNA-binding protein 43 transgenic mice carrying a glial fibrillary acidic protein-luciferase reporter revealed that the behavioural defects were preceded by induction of astrogliosis, a finding consistent with a role for reactive astrocytes in amyotrophic lateral sclerosis pathogenesis. These novel transactive response DNA-binding protein 43 transgenic mice mimic several characteristics of human amyotrophic lateral sclerosis-frontotemporal lobar degeneration and they should provide valuable animal models for testing therapeutic approaches.

[1]  J. Kriz,et al.  Treatment with minocycline after disease onset alters astrocyte reactivity and increases microgliosis in SOD1 mutant mice , 2011, Experimental Neurology.

[2]  Gene W. Yeo,et al.  Long pre-mRNA depletion and RNA missplicing contribute to neuronal vulnerability from loss of TDP-43 , 2011, Nature Neuroscience.

[3]  T. Tokuda,et al.  Elevated CSF TDP-43 levels in amyotrophic lateral sclerosis: Specificity, sensitivity, and a possible prognostic value , 2011, Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases.

[4]  Axel Petzold,et al.  A method to solubilise protein aggregates for immunoassay quantification which overcomes the neurofilament “hook” effect , 2011, Journal of Neuroscience Methods.

[5]  D. Burns,et al.  Progressive motor weakness in transgenic mice expressing human TDP-43 , 2010, Neurobiology of Disease.

[6]  L. Petrucelli,et al.  Wild-Type Human TDP-43 Expression Causes TDP-43 Phosphorylation, Mitochondrial Aggregation, Motor Deficits, and Early Mortality in Transgenic Mice , 2010, The Journal of Neuroscience.

[7]  Bruce L. Miller,et al.  Frontotemporal lobar degeneration , 2010, CNS drugs.

[8]  S. Pereson,et al.  TDP-43 transgenic mice develop spastic paralysis and neuronal inclusions characteristic of ALS and frontotemporal lobar degeneration , 2010, Proceedings of the National Academy of Sciences.

[9]  S. Scherer,et al.  A novel recessive Nefl mutation causes a severe, early‐onset axonal neuropathy , 2009, Annals of neurology.

[10]  N. Cairns,et al.  TDP-43 mutant transgenic mice develop features of ALS and frontotemporal lobar degeneration , 2009, Proceedings of the National Academy of Sciences.

[11]  A Florence Keller,et al.  Live imaging of amyotrophic lateral sclerosis pathogenesis: Disease onset is characterized by marked induction of GFAP in Schwann cells , 2009, Glia.

[12]  L. Petrucelli,et al.  Aberrant cleavage of TDP-43 enhances aggregation and cellular toxicity , 2009, Proceedings of the National Academy of Sciences.

[13]  D. Cleveland,et al.  Rethinking ALS: The FUS about TDP-43 , 2009, Cell.

[14]  K. Eggan,et al.  Human embryonic stem cell-derived motor neurons are sensitive to the toxic effect of glial cells carrying an ALS-causing mutation. , 2008, Cell stem cell.

[15]  W. Seeley,et al.  Selective functional, regional, and neuronal vulnerability in frontotemporal dementia , 2008, Current opinion in neurology.

[16]  I-Fan Wang,et al.  TDP-43 Overexpression Enhances Exon 7 Inclusion during the Survival of Motor Neuron Pre-mRNA Splicing* , 2008, Journal of Biological Chemistry.

[17]  J. Julien,et al.  Modest loss of peripheral axons, muscle atrophy and formation of brain inclusions in mice with targeted deletion of gigaxonin exon 1 , 2008, Journal of neurochemistry.

[18]  J. Julien,et al.  Als2 mRNA splicing variants detected in KO mice rescue severe motor dysfunction phenotype in Als2 knock-down zebrafish. , 2008, Human molecular genetics.

[19]  D. Geschwind,et al.  Novel Mutations in TARDBP (TDP-43) in Patients with Familial Amyotrophic Lateral Sclerosis , 2008, PLoS genetics.

[20]  B. McConkey,et al.  TARDBP mutations in individuals with sporadic and familial amyotrophic lateral sclerosis , 2008, Nature Genetics.

[21]  Murray Grossman,et al.  TARDBP mutations in amyotrophic lateral sclerosis with TDP-43 neuropathology: a genetic and histopathological analysis , 2008, The Lancet Neurology.

[22]  J. Morris,et al.  TDP‐43 A315T mutation in familial motor neuron disease , 2008, Annals of neurology.

[23]  A. Kakita,et al.  TDP‐43 mutation in familial amyotrophic lateral sclerosis , 2008, Annals of neurology.

[24]  Xun Hu,et al.  TDP-43 Mutations in Familial and Sporadic Amyotrophic Lateral Sclerosis , 2008, Science.

[25]  M. Strong,et al.  An Aggregate-Inducing Peripherin Isoform Generated through Intron Retention Is Upregulated in Amyotrophic Lateral Sclerosis and Associated with Disease Pathology , 2008, The Journal of Neuroscience.

[26]  L. Zinman,et al.  Evidence That TDP-43 is Not the Major Ubiquitinated Target Within the Pathological Inclusions of Amyotrophic Lateral Sclerosis , 2007, Journal of neuropathology and experimental neurology.

[27]  J. Trojanowski,et al.  TDP-43: a novel neurodegenerative proteinopathy , 2007, Current Opinion in Neurobiology.

[28]  J. Morris,et al.  TDP-43 in familial and sporadic frontotemporal lobar degeneration with ubiquitin inclusions. , 2007, The American journal of pathology.

[29]  Hynek Wichterle,et al.  Astrocytes expressing ALS-linked mutated SOD1 release factors selectively toxic to motor neurons , 2007, Nature Neuroscience.

[30]  J. Julien.  ALS: astrocytes move in as deadly neighbors , 2007, Nature Neuroscience.

[31]  A. Roberts,et al.  Aged APP23 mice show a delay in switching to the use of a strategy in the Barnes maze , 2007, Behavioural Brain Research.

[32]  Kevin Eggan,et al.  Non–cell autonomous effect of glia on motor neurons in an embryonic stem cell–based ALS model , 2007, Nature Neuroscience.

[33]  K. Talbot,et al.  Recent advances in the genetics of amyotrophic lateral sclerosis and frontotemporal dementia: common pathways in neurodegenerative disease. , 2006, Human molecular genetics.

[34]  Bruce L. Miller,et al.  Ubiquitinated TDP-43 in Frontotemporal Lobar Degeneration and Amyotrophic Lateral Sclerosis , 2006, Science.

[35]  E. Buratti,et al.  Depletion of TDP 43 overrides the need for exonic and intronic splicing enhancers in the human apoA-II gene , 2005, Nucleic acids research.

[36]  L. Barbeito,et al.  A role for astrocytes in motor neuron loss in amyotrophic lateral sclerosis , 2004, Brain Research Reviews.

[37]  J. Hodges,et al.  Clinicopathological correlates in frontotemporal dementia , 2004, Annals of neurology.

[38]  B. Miller,et al.  Are amyotrophic lateral sclerosis patients cognitively normal? , 2003, Neurology.

[39]  J. Julien,et al.  A neurotoxic peripherin splice variant in a mouse model of ALS , 2003, The Journal of cell biology.

[40]  J. Julien,et al.  Induction of peripherin expression in subsets of brain neurons after lesion injury or cerebral ischemia , 2002, Brain Research.

[41]  T. Dörk,et al.  Nuclear factor TDP‐43 and SR proteins promote in vitro and in vivo CFTR exon 9 skipping , 2001, The EMBO journal.

[42]  M. Strong,et al.  Characterization of Neuronal Intermediate Filament Protein Expression in Cervical Spinal Motor Neurons in Sporadic Amyotrophic Lateral Sclerosis (ALS) , 2000, Journal of neuropathology and experimental neurology.

[43]  J. Julien,et al.  Altered Ionic Conductances in Axons of Transgenic Mouse Expressing the Human Neurofilament Heavy Gene: A Mouse Model of Amyotrophic Lateral Sclerosis , 2000, Experimental Neurology.

[44]  J. Julien,et al.  Late Onset Death of Motor Neurons in Mice Overexpressing Wild-Type Peripherin , 1999, The Journal of cell biology.

[45]  Peter F. Johnson,et al.  Interleukin‐6 Induces Expression of Peripherin and Cooperates with Trk Receptor Signaling to Promote Neuronal Differentiation in PC12 Cells , 1996, Journal of neurochemistry.

[46]  D Harrich,et al.  Cloning and characterization of a novel cellular protein, TDP-43, that binds to human immunodeficiency virus type 1 TAR DNA sequence motifs , 1995, Journal of virology.

[47]  D. Schiffer,et al.  Peripherin immunoreactive structures in amyotrophic lateral sclerosis. , 1993, Laboratory investigation; a journal of technical methods and pathology.

[48]  A. Hays,et al.  Peripherin and Neurofilament Protein Coexist in Spinal Spheroids of Motor Neuron Disease , 1992, Journal of neuropathology and experimental neurology.

[49]  S. Carpenter.  Proximal axonal enlargement in motor neuron disease , 1968, Neurology.