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, 2019 01 08.
Article
em En
| MEDLINE
| ID: mdl-30625319
ABSTRACT
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-43M337V and TDP-43G298S 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.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Proteínas de Ligação a DNA
/
Esclerose Lateral Amiotrófica
/
Neurônios Motores
Tipo de estudo:
Etiology_studies
Limite:
Animals
Idioma:
En
Revista:
Cell Rep
Ano de publicação:
2019
Tipo de documento:
Article