In vitro prion-like behaviour of TDP-43 in ALS

NEUROBIOLOGY OF DISEASE

卷:96

Article

Smethurst, Phillip¹  Newcombe, Jia²  Troakes, Claire³  Simone, Roberto¹  Chen, Yun-Ru⁴  Patani, Rickie¹  Sidle, Katie¹ 

[1] UCL, Inst Neurol, Dept Mol Neurosci, Queen Sq House,Queen Sq, London WC1N 3BG, England

[2] UCL, Inst Neurol, Dept Neuroinflammat, NeuroResource, 1 Wakefield St, London WC1N 1PJ, England

[3] Kings Coll London, London Neurodegenerat Dis Brain Bank, Inst Psychiat Psychol & Neurosci, DeCrispigny Pk, London, England

[4] Acad Sinica, Genom Res Ctr, 128 Acad Rd,Sect 2, Taipei 115, Taiwan

关键词: ALS;    Prion-like disease;    Protein misfolding;    TDP-43;    Seeding;    Propagation;   

DOI  :  10.1016/j.nbd.2016.08.007

来源: Elsevier

【 摘 要 】

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. (C) 2016 The Authors. Published by Elsevier Inc.

【 授权许可】

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