Unknown

Dataset Information

0

Motor-Coordinative and Cognitive Dysfunction Caused by Mutant TDP-43 Could Be Reversed by Inhibiting Its Mitochondrial Localization.


ABSTRACT: Dominant missense mutations in TAR DNA-binding protein 43 (TDP-43) cause amyotrophic lateral sclerosis (ALS), and the cytoplasmic accumulation of TDP-43 represents a pathological hallmark in ALS and frontotemporal lobar degeneration (FTD). Behavioral investigation of the transgenic mouse model expressing the disease-causing human TDP-43 M337V mutant (TDP-43M337V mice) is encumbered by premature death in homozygous transgenic mice and a reported lack of phenotype assessed by tail elevation and footprint in hemizygous transgenic mice. Here, using a battery of motor-coordinative and cognitive tests, we report robust motor-coordinative and cognitive deficits in hemizygous TDP-43M337V mice by 8 months of age. After 12 months of age, cortical neurons are significantly affected by the mild expression of mutant TDP-43, characterized by cytoplasmic TDP-43 mislocalization, mitochondrial dysfunction, and neuronal loss. Compared with age-matched non-transgenic mice, TDP-43M337V mice demonstrate a similar expression of total TDP-43 but higher levels of TDP-43 in mitochondria. Interestingly, a TDP-43 mitochondrial localization inhibitory peptide abolishes cytoplasmic TDP-43 accumulation, restores mitochondrial function, prevents neuronal loss, and alleviates motor-coordinative and cognitive deficits in adult hemizygous TDP-43M337V mice. Thus, this study suggests hemizygous TDP-43M337V mice as a useful animal model to study TDP-43 toxicity and further consolidates mitochondrial TDP-43 as a novel therapeutic target for TDP-43-linked neurodegenerative diseases.

SUBMITTER: Wang W 

PROVIDER: S-EPMC5363201 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

altmetric image

Publications

Motor-Coordinative and Cognitive Dysfunction Caused by Mutant TDP-43 Could Be Reversed by Inhibiting Its Mitochondrial Localization.

Wang Wenzhang W   Arakawa Hiroyuki H   Wang Luwen L   Okolo Ogoegbunam O   Siedlak Sandra L SL   Jiang Yinfei Y   Gao Ju J   Xie Fei F   Petersen Robert B RB   Wang Xinglong X  

Molecular therapy : the journal of the American Society of Gene Therapy 20170104 1


Dominant missense mutations in TAR DNA-binding protein 43 (TDP-43) cause amyotrophic lateral sclerosis (ALS), and the cytoplasmic accumulation of TDP-43 represents a pathological hallmark in ALS and frontotemporal lobar degeneration (FTD). Behavioral investigation of the transgenic mouse model expressing the disease-causing human TDP-43 M337V mutant (TDP-43<sup>M337V</sup> mice) is encumbered by premature death in homozygous transgenic mice and a reported lack of phenotype assessed by tail eleva  ...[more]

Similar Datasets

| S-EPMC11603663 | biostudies-literature
| S-EPMC8361416 | biostudies-literature
| S-EPMC3216869 | biostudies-other
| S-EPMC11844547 | biostudies-literature
| S-EPMC8423945 | biostudies-literature
| S-EPMC2478749 | biostudies-literature
| S-EPMC7260973 | biostudies-literature
| S-EPMC9040199 | biostudies-literature
| S-EPMC7138241 | biostudies-literature
| S-EPMC3248298 | biostudies-literature