ALS-linked mutant TDP-43 in oligodendrocytes induces oligodendrocyte damage and exacerbates motor dysfunction in mice.

ABSTRACT: Nuclear clearance and cytoplasmic aggregation of TAR DNA-binding protein of 43 kDa (TDP-43) are pathological hallmarks of amyotrophic lateral sclerosis (ALS) and its pathogenic mechanism is mediated by both loss-of-function and gain-of-toxicity of TDP-43. However, the role of TDP-43 gain-of-toxicity in oligodendrocytes remains unclear. To investigate the impact of excess TDP-43 on oligodendrocytes, we established transgenic mice overexpressing the ALS-linked mutant TDP-43^M337V in oligodendrocytes through crossbreeding with Mbp-Cre mice. Two-step crossbreeding of floxed TDP-43^M337V and Mbp-Cre mice resulted in the heterozygous low-level systemic expression of TDP-43^M337V with (Cre-positive) or without (Cre-negative) oligodendrocyte-specific overexpression of

SUBMITTER: Horiuchi M 

PROVIDER: S-EPMC11603663 | biostudies-literature | 2024 Nov

REPOSITORIES: biostudies-literature