title: In vitro prion-like behaviour of TDP-43 in ALS.
abstract: Amyotrophic lateral sclerosis (ALS) is the most common form of motor neuron disease (MND), and >95% of familial and sporadic cases involve the deposition of insoluble aggregated, phosphorylated and cleaved TDP-43 protein. Accumulating clinical and biological evidence now indicates that ALS bears a number of similarities to the prion diseases, with TDP-43 acting as a misfolded 'prion-like' protein demonstrating similar underlying pathobiology. Here we systematically address the hypothesis that ALS is a prion-like disorder. First we demonstrate that TDP-43 demonstrates seeded polymerisation in vitro directly from both ALS brain and spinal cord. We next show that the seeding of TDP-43 results in the formation of characteristic insoluble, aggregated, and phosphorylated TDP-43 pathology that directly recapitulates the morphological diversity of TDP-43 inclusions detected in ALS patient CNS tissue. We next demonstrate that this reaction can be serially propagated to produce increasing amounts of phosphorylated TDP-43 pathology, and that aggregates can spread from cell to cell in an analogous fashion to that seen in the prion diseases. Finally, we reproduced our findings in a murine motor neuron-like cell line (NSC-34), where the seeding of TDP-43 induces the formation of TDP-43 oligomers and reduced cell viability. These findings may guide therapeutic strategies in this rapidly progressive and invariably fatal disease.
authors: Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square House, Queen Square, London WC1N 3BG, United Kingdom.
authors: Phillip
authors: P
authors: Smethurst
authors: NeuroResource, UCL Institute of Neurology, Department of Neuroinflammation, 1 Wakefield Street, London WC1N 1PJ, United Kingdom.
authors: Jia
authors: J
authors: Newcombe
authors: London Neurodegenerative Diseases Brain Bank, Institute of Psychiatry, Psychology and Neuroscience, King's College London, DeCrispigny Park, London, United Kingdom.
authors: Claire
authors: C
authors: Troakes
authors: Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square House, Queen Square, London WC1N 3BG, United Kingdom.
authors: Roberto
authors: R
authors: Simone
authors: Genomics Research Center, Academia Sinica, 128, Academia Road, Section 2, Nankang District, Taipei 115, Taiwan.
authors: Yun-Ru
authors: YR
authors: Chen
authors: Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square House, Queen Square, London WC1N 3BG, United Kingdom.
authors: Rickie
authors: R
authors: Patani
authors: Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square House, Queen Square, London WC1N 3BG, United Kingdom. Electronic address: Katie.sidle@uclh.nhs.uk.
authors: Katie
authors: K
authors: Sidle
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000473:pathology*; D000818:Animals; D001344:Autopsy; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D018920:Coculture Techniques; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D009046:Motor Neurons / Q000378:metabolism; D009447:Neuroblastoma / Q000473:pathology; D000072002:Prion Proteins / Q000378:metabolism*; D013116:Spinal Cord / Q000378:metabolism* / Q000473:pathology; D014162:Transfection
chemical_list: D004268:DNA-Binding Proteins; D000072002:Prion Proteins; C000598624:TARDBP protein, human; D049452:Green Fluorescent Proteins
keywords: ALS; Prion-like disease; Propagation; Protein misfolding; Seeding; TDP-43