TDP-43 accelerates age-dependent degeneration of interneurons

• Published in: Scientific reports Vol. 7; no. 1; pp. 14972 - 13
• Main Authors: Tsuiji, Hitomi, Inoue, Ikuyo, Takeuchi, Mari, Furuya, Asako, Yamakage, Yuko, Watanabe, Seiji, Koike, Masato, Hattori, Mitsuharu, Yamanaka, Koji
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 02-11-2017; Nature Publishing Group
• Subjects: 38; 38/61; 42/41; 631/378/87; 64; 64/60; 692/617/375/132; Accumulation; Age; Aggregates; Aging; Amyotrophic lateral sclerosis; Animal models; Calretinin; Cytoplasm; Dementia disorders; Frontotemporal dementia; Hippocampus; Humanities and Social Sciences; Interneurons; multidisciplinary; Neurodegeneration; Neurodegenerative diseases; Oxidative stress; Parvalbumin; Phenotypes; Ribonucleic acid; Risk factors; RNA; RNA-binding protein; Rodents; Science; Science (multidisciplinary); Transgenic animals; Transgenic mice; γ-Aminobutyric acid
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-017-14966-w

TDP-43 is an RNA-binding protein important for many aspects of RNA metabolism. Abnormal accumulation of TDP-43 in the cytoplasm of affected neurons is a pathological hallmark of the neurodegenerative diseases frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Several transgenic mouse models have been generated that recapitulate defects in TDP-43 accumulation, thus causing neurodegeneration and behavioural impairments. While aging is the key risk factor for neurodegenerative diseases, the specific effect of aging on phenotypes in TDP-43 transgenic mice has not been investigated. Here, we analyse age-dependent changes in TDP-43 transgenic mice that displayed impaired memory. We found the accumulation of abundant poly-ubiquitinated protein aggregates in the hippocampus of aged TDP-43 transgenic mice. Intriguingly, the aggregates contained some interneuron-specific proteins such as parvalbumin and calretinin, suggesting that GABAergic interneurons were degenerated in these mice. The abundance of aggregates significantly increased with age and with the overexpression of TDP-43. Gene array analyses in the hippocampus and other brain areas revealed dysregulation in genes linked to oxidative stress and neuronal function in TDP-43 transgenic mice. Our results indicate that the interneuron degeneration occurs upon aging, and TDP-43 accelerates age-dependent neuronal degeneration, which may be related to the impaired memory of TDP-43 transgenic mice.