期刊
NEUROBIOLOGY OF DISEASE
卷 115, 期 -, 页码 167-181出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.nbd.2018.03.010
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
资金
- Helmholtz Virtual Institute [VH-VI-510]
- MeDDrive program of the Medical Faculty at the Technische Universitat Dresden
- Center for Regenerative Therapies Dresden
- Roland Ernst Stiftung Saxony
- BIOCREA GMBH
- NOMIS foundation
- Stiftung Hochschulmedizin Dresden
- Deutsche Gesellschaft fur Muskelerkrankungen [He 2/2]
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.
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