Age-dependent neurodegeneration and organelle transport deficiencies in mutant TDP43 patient-derived neurons are independent of TDP43 aggregation

NEUROBIOLOGY OF DISEASE

卷:115

Article

Kreiter, N.^1,2  Pal, A.¹  Lojewski, X.¹  Corcia, P.⁴  Naujock, M.^5,7  Reinhardt, P.^3,8  Sterneckert, J.³  Petri, S.⁵  Wegner, F.⁵  Storch, A.^1,2,3,6  Hermann, A.^1,2,3 

[1] Tech Univ Dresden, Dept Neurol, Fetscherstr 74, D-01307 Dresden, Germany

[2] German Ctr Neurodegenerat Dis DZNE, Dresden, Germany

[3] Tech Univ Dresden, Ctr Regenerat Therapies Dresden CRTD, Dresden, Germany

[4] CHU Tours, Ctr Expert SLA & Malad Motoneurone, 2 Blvd Tonnelle, F-37044 Tours 1, France

[5] Hannover Med Sch, Dept Neurol, Hannover, Germany

[6] Univ Rostock, Dept Neurol, Rostock, Germany

[7] Boehringer Ingelheim Pharma GmbH & Co KG, CNS Res Dept, Ingelheim, Germany

[8] AbbVie Germany GmbH & Co KG, Neurosci Discovery, Ludwigshafen, Germany

关键词: Amyotrophic lateral sclerosis;    TAR DNA binding protein 43;    TARDBP;    Neurodegeneration;    Mitochondria;    Lysosomes;    Live cell imaging;    Axonopathy;    Neurofilament;    DNA damage;    Nuclear stress;    hnRNPK;   

DOI  :  10.1016/j.nbd.2018.03.010

来源: Elsevier

【 摘 要 】

TAR DNA-binding protein 43 (TDP43) plays a significant role in familiar and sporadic amyotrophic lateral sclerosis (ALS). The diverse postulated mechanisms by which TDP43 mutations cause the disease are not fully understood. Human wildtype and TDP43 S393L and G294V mutant spinal motor neuron cultures were differentiated from patient-derived iPSCs. Mutant hTDP43 and wildtype motor neuron cultures did not differ in neuron differentiation capacity during early maturation stage. During aging we detected a dramatic neurodegeneration including neuron loss and pathological neurofilament abnormalities only in TDP43 mutant cultures. Additionally mitochondria and lysosomes of aging spinal motor neurons revealed robust TDP43 mutation dependent abnormal phenotypes in size, shape, speed and motility which all appeared without TDP43 mislocalization or aggregation formation. Furthermore, D-sorbitol known to induce stress granules and cytoplasmic mislocalization of TDP43 rescued axonal trafficking phenotypes without signs of TDP43 mislocalization or aggregation formation. Our data indicate TDP43 mutation-dependent but cytosolic aggregation-independent mechanisms of motor neuron degeneration in TDP43 ALS.

【 授权许可】

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