Model Mice Mimic ALS

Using a transgenic mouse model, scientists have found the accumulation of TPD-43 in neurons is related to motor and memory deficits.

AsianScientist (Nov. 27, 2017) – Scientists in Japan have developed a transgenic mouse model to better understand age-related neurological diseases. They published their findings in Scientific Reports.

Neurodegenerative diseases are incurable and debilitating conditions that result in progressive degeneration and death of neurons, leading to problems with movement or mental functioning. Examples include Alzheimer’s disease, Parkinson’s disease, 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 temporal lobes of the brain.

Neurodegenerative diseases are known to have common cellular and molecular mechanisms, including protein misfolding and aggregation. In nearly half of all FTD cases and in 97 percent of all ALS cases, there is an accumulation of the protein TDP-43 in neurons. Several mutations in TDP-43 have been identified as a cause of some hereditary and sporadic ALS and FTD cases. However, the specific effect of aging on TDP-43 has not been investigated.

In this study, a team of researchers at Nagoya University in Japan developed transgenic mice expressing elevated levels of TDP-43 to replicate the pathology of sporadic ALS and FTD. TDP-43 is an important protein involved in various aspects of the metabolism of RNA.

They then performed serial behavioral tests on the mice, including the Y-maze test (to assess working memory), the rotarod test (motor function and learning), as well as the contextual and cued fear condition test (fear learning and memory). They found that the abundance of protein aggregates in neurons drastically increased with the overexpression of TDP-43 and with age. Gene analyses of the hippocampus and other brain areas further revealed dysregulation in the genes linked to reactive oxygen species regulation and neuronal function.

“In transgenic mice expressing unusually high levels of TDP-43 we observed memory and motor deficits,” said Yamanaka. “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.”

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

The article can be found at: Tsuiji et al. (2017) TDP-43 Accelerates Age-Dependent Degeneration of Interneurons.


Source: Nagoya University.
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