Deadly Combination In Neurodegenerative Diseases Revealed Neuroscience

Summary: A new mouse model has been developed that captures the pathology of sporadic neurodegenerative diseases.

Source: Nagoya University.

Neurodegenerative diseases are incurable and debilitating conditions that result in progressive degeneration and death of nerve cells, which leads to problems with movement or mental functioning. Examples include Alzheimer’s, Parkinson’s, amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). ALS is characterized by degeneration of motor neurons, while FTD is characterized by progressive neuronal loss mostly in the frontal and/or temporal lobes of the brain.

Neurodegenerative diseases are increasingly being realized to have common cellular and molecular mechanisms including protein misfolding and aggregation. In nearly half of all FTD cases and in 97% of the ALS cases, there is an accumulation of the protein TDP-43 in the affected neurons, the basic working units of the nervous system.

In a non-disease state, TDP-43 is an important protein involved in various aspects of the metabolism of RNA, a molecule essential in various biological roles in the regulation and expression of genes. In a disease state, several mutations in TDP-43 have been identified as a cause of some hereditary and sporadic ALS and FTD cases. While this underscores the critical role of TDP-43 in the development of these conditions, the specific effect of aging on TDP-43 has not been investigated. This prompted a team of scientists centered in Nagoya, Japan, to delve deep into the subject. Their findings were recently published in Scientific Reports.

For their investigation, the researchers first developed a disease model of transgenic mice expressing elevated levels of TDP-43 to capture the pathology of sporadic ALS/FTD. They then performed serial behavioral tests on the mice, including Y-maze test (to assess working memory), rotarod test (motor function and learning), and contextual and cued fear condition test (fear learning and memory).

Two lines captured with eye-tracking technology show that twins will follow a similar pattern with their eyes when shown the same image. NeuroscienceNews.com image is credited to Koomi Sung.

“In transgenic mice expressing unusually high levels of TDP-43 we observed memory and motor deficits,” study corresponding author Koji Yamanaka says. “We also noticed an accumulation of debris of interneurons – the cells that serve as a connection between sensory and motor pathways for reflexes – in the hippocampus, which is responsible for memory storage.”

Notably, the abundance of aggregates drastically increased with age and with the overexpression of TDP-43. Gene analyses of the hippocampus and other brain areas revealed dysregulation in the genes linked to manifestation of damaging reactive oxygen species and neuronal function.

“The degeneration of interneurons as seen in our mouse model could be the very early age-accelerated changes observed in the diseases,” Yamanaka says. “Moreover, it has been reported that inhibitory interneuron deficits link altered network activity and cognitive dysfunction in models of Alzheimer’s disease. Therefore, this particular mouse model may be useful for studying neurological diseases accelerated by aging.”

Additional researchers on the paper are Patrick D. Quinn, a postdoctoral student in the IU Bloomington Department of Psychological and Brain Sciences, and Sven Bölte, Paul Lichtenstein and Terje Falck-Ytter of the Karolinska Institute.

Funding: This study was supported by Ministry of Education, Culture, and Sports, Science, and Technology of Japan, Japan Agency for Medical Research and Development, Japan Science and Technology Agency, Japan ALS association.

Source: Koomi Sung – Nagoya University
Publisher: Organized by NeuroscienceNews.com.
Image Source: NeuroscienceNews.com image is credited to Koomi Sung.
Original Research: Full open access research for “TDP-43 accelerates age-dependent degeneration of interneurons” by Hitomi Tsuiji, Ikuyo Inoue, Mari Takeuchi, Asako Furuya, Yuko Yamakage, Seiji Watanabe, Masato Koike, Mitsuharu Hattori & Koji Yamanaka in Scientific Repors. Published online November 2 2017 doi:10.1038/s41598-017-14966-w

Abstract

TDP-43 accelerates age-dependent degeneration of interneurons

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.

“TDP-43 accelerates age-dependent degeneration of interneurons” by Hitomi Tsuiji, Ikuyo Inoue, Mari Takeuchi, Asako Furuya, Yuko Yamakage, Seiji Watanabe, Masato Koike, Mitsuharu Hattori & Koji Yamanaka in Scientific Repors. Published online November 2 2017 doi:10.1038/s41598-017-14966-w

Source: Neuroscience News