Elucidation of the Mechanism Behind Frontotemporal Lobar Degeneration

Loss of VCP Gene Function During Neural Development causes the disease

The research groups led by Associate Professor Masaki Sone from the Faculty of Science, Toho University, and Professor Hitoshi Okazawa from Institute of Science Tokyo and Maastricht University in the Netherlands uncovered the mechanism underlying frontotemporal lobar degeneration (FTLD) caused by variants in the valosin-containing protein (VCP) gene. Using a fruit fly model, this study revealed key insights into the disease, laying the groundwork for future therapeutic development.
This research was supported by a grant-in-aid for scientific research (C) from the Japan Society for the Promotion of Science (JSPS) and the Joint Usage/Research Program of the Medical Research Institute, Institute of Science Tokyo.
The findings were published on December 23, 2024, in Disease Models & Mechanisms.

Morphology of the mushroom body of the FTLD (frontotemporal lobar degeneration) model fruit flies. Alterations in the morphology of mushroom bodies in VCP/TER94 knockdown flies were rescued by the coexpression of wild-type VCP/TER94, but to a lesser extent by the coexpression of disase-associated mutant VCP/TER94.

Key Points:

Mechanisms underlying FTLD caused by variants in the VCP gene.
The abnormal proliferation of neural stem cells during neural development, triggered by the loss of VCP gene function, led to neurodegenerative symptoms.
This study provides fundamental knowledge for developing future treatments for FTLD.

Research Overview:
FTLD is a major cause of dementia with a prevalence second only to that of Alzheimer’s disease and Lewy body dementia. Mutations in the VCP gene are known to cause hereditary FTLD. Previous collaborative studies, including those by Professor Hitoshi Okazawa’s team at Institute of Science Tokyo and Associate Professor Masaki Sone’s team at Toho University, identified that DNA damage during the fetal stage affects the onset of FTLD after decades of using a mouse model (Homma et al., Life Sci. Alliance 2021).
Here, we employed a fruit fly model to show that the loss of VCP gene function leads to abnormal proliferation of neural stem cells during the developmental stage. This abnormality has been identified as a direct cause of neurodegenerative symptoms. These findings offer fundamental insights for the development of new treatments for FTLD.

Journal:
Disease Models & Mechanisms (December 23, 2024)

Title:
Loss of function of VCP/TER94 causes neurodegeneration

Authors:
Kohei Tsumaki, Christian J. F. Bertens, Minoru Nakayama, Saya Kato, Yuki Jonao, Ayu Kuribayashi, Konosuke Sato, Shota Ishiyama, Momoko Asakawa, Riko Aihara, Yuki Yoshioka, Hidenori Homma, Hikari Tanaka, Kyota Fujita, Hitoshi Okazawa, and Masaki Sone*

DOI:
10.1242/dmm.050359

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