| First Author | Ebstein SY | Year | 2019 |
| Journal | Cell Rep | Volume | 26 |
| Issue | 2 | Pages | 364-373.e4 |
| PubMed ID | 30625319 | Mgi Jnum | J:283769 |
| Mgi Id | MGI:6377893 | Doi | 10.1016/j.celrep.2018.12.045 |
| Citation | Ebstein SY, et al. (2019) Mutant TDP-43 Causes Early-Stage Dose-Dependent Motor Neuron Degeneration in a TARDBP Knockin Mouse Model of ALS. Cell Rep 26(2):364-373.e4 |
| abstractText | Rare mutations in TARDBP, the gene encoding TDP-43, cause amyotrophic lateral sclerosis (ALS), and TDP-43 pathology is seen in a large majority of ALS patients, suggesting a central pathogenic role of this regulatory protein. The consequences of TARDBP mutations on TDP-43 function and the mechanism by which mutant TDP-43 causes neurodegeneration remain uncertain. Here, we characterize a series of knockin mice carrying disease-associated TARDBP mutations. We demonstrate that TDP-43(M337V) and TDP-43(G298S) are functional, each rescuing the lethality of TDP-43 loss of function. In a subset of aged heterozygous knockin mice, we observe the earliest signs of selective motor neuron degeneration, demonstrating that physiological levels of mutant TDP-43 are sufficient to initiate disease. Furthermore, aged homozygous mutants develop selective, asymmetric motor neuron pathology, providing in vivo evidence of TDP-43 dose-dependent neurotoxicity. These knockin mice represent a faithful in vivo model of early-stage ALS and enable future exploration of TDP-43-associated neurodegeneration. |
