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

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

来源：Molecular Therapy, 2017, 25(1): 127-139.

DOI：10.1016/j.ymthe.2016.10.013

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(M337V) 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-43(M337V) 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-43(M337V) 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 mitochondria' function, prevents neuronal loss, and alleviates motor-coordinative and cognitive deficits in adult hemizygous TDP-43(M337V) mice. Thus, this study suggests hemizygous TDP-43(M337V) mice as a useful animal model to study TDP-43 toxicity and further consolidates mitochondria' TDP-43 as a novel therapeutic target for TDP-43-linked neurodegenerative diseases.

• 出版日期2017-1-4