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Updated: Nov 2, 2025
Assessing Cell Cycle Progression of Neural Stem and Progenitor Cells in the Mouse Developing Brain after Genotoxic Stress
Published on: May 7, 2014
DNA damage in embryonic neural stem cell determines FTLDs' fate via early-stage neuronal necrosis
Hidenori Homma1, Hikari Tanaka1, Meihua Jin1
1Department of Neuropathology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.
Abstract:
The early-stage pathologies of frontotemporal lobal degeneration (FTLD) remain largely unknown. In VCPT262A-KI mice carrying VCP gene mutation linked to FTLD, insufficient DNA damage repair in neural stem/progenitor cells (NSCs) activated DNA-PK and CDK1 that disabled MCM3 essential for the G1/S cell cycle transition. Abnormal neural exit produced neurons carrying over unrepaired DNA damage and induced early-stage transcriptional repression-induced atypical cell death (TRIAD) necrosis accompanied by the specific markers pSer46-MARCKS and YAP. In utero gene therapy expressing normal VCP or non-phosphorylated mutant MCM3 rescued DNA damage, neuronal necrosis, cognitive function, and TDP43 aggregation in adult neurons of VCPT262A-KI mice, whereas similar therapy in adulthood was less effective. The similar early-stage neuronal necrosis was detected in PGRNR504X-KI, CHMP2BQ165X-KI, and TDPN267S-KI mice, and blocked by embryonic treatment with AAV-non-phospho-MCM3. Moreover, YAP-dependent necrosis occurred in neurons of human FTLD patients, and consistently pSer46-MARCKS was increased in cerebrospinal fluid (CSF) and serum of these patients. Collectively, developmental stress followed by early-stage neuronal necrosis is a potential target for therapeutics and one of the earliest general biomarkers for FTLD.
Insights
Early-stage frontotemporal lobar degeneration (FTLD) involves DNA damage and neuronal death in neural stem cells. Gene therapy during development effectively treated FTLD models, suggesting early intervention and biomarkers for FTLD.
Area of Science:
- Neuroscience
- Genetics
- Cell Biology
Background:
- Early-stage pathologies of frontotemporal lobar degeneration (FTLD) are poorly understood.
- Genetic mutations in VCP, PGRN, CHMP2B, and TDP are linked to FTLD.
- Neural stem/progenitor cells (NSCs) are crucial for brain development.
Purpose of the Study:
- To investigate the early-stage mechanisms of FTLD.
- To identify potential therapeutic targets and biomarkers for FTLD.
Main Methods:
- Utilized VCPT262A-KI mice and other FTLD-model mice.
- Employed in utero and adult gene therapy with AAV vectors.
- Analyzed DNA damage, cell cycle progression, neuronal death markers (pSer46-MARCKS, YAP), cognitive function, and TDP43 aggregation.
- Measured biomarkers in cerebrospinal fluid (CSF) and serum of human FTLD patients.
Main Results:
- FTLD models showed insufficient DNA repair in NSCs, activating DNA-PK/CDK1 and disabling MCM3, leading to unrepaired DNA damage in neurons.
- This resulted in transcriptional repression-induced atypical cell death (TRIAD) necrosis, marked by pSer46-MARCKS and YAP.
- In utero gene therapy targeting VCP or MCM3 rescued FTLD phenotypes in mice, while adult therapy was less effective.
- Similar early-stage neuronal necrosis was observed in other FTLD models and blocked by embryonic AAV-non-phospho-MCM3 treatment.
- YAP-dependent necrosis and increased pSer46-MARCKS were found in human FTLD patients' neurons, CSF, and serum.
Conclusions:
- Developmental stress and early-stage neuronal necrosis are key pathological events in FTLD.
- Targeting these early events, particularly during development, holds therapeutic potential for FTLD.
- pSer46-MARCKS and YAP are promising early biomarkers for FTLD.
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