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

Wenzhang Wang, Hiroyuki Arakawa, Luwen Wang, Ogoegbunam Okolo, Sandra L. Siedlak, Yinfei Jiang, Ju Gao, Fei Xie, Robert B. Petersen, Xinglong Wang

Research output: Contribution to journalArticlepeer-review

52 Scopus citations


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.

Original languageEnglish
Pages (from-to)127-139
Number of pages13
JournalMolecular Therapy
Issue number1
StatePublished - Jan 4 2017


  • ALS
  • FTD
  • TDP-43
  • cognitive deficit
  • mitochondrial dysfunction
  • motor dysfunction
  • neurodegeneration
  • transgenic mice


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