DNA damage in embryonic neural stem cell determines FTLDs' fate via early-stage neuronal necrosis

H. Homma, H. Tanaka, M.H. Jin, X.C. Jin, Y. Huang, Y. Yoshioka, C.J.F. Bertens, K. Tsumaki, K. Kondo, H. Shiwaku, K. Tagawa, H. Akalsu, N. Atsuta, M. Katsuno, K. Furukawa, A. Ishiki, M. Waragai, G. Ohtomo, A. Iwata, T. YokotaH. Inoue, H. Arai, G. Sobue, M. Sone, K. Fujita, H. Okazawa*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

2 Citations (Web of Science)

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 ne-crosis, cognitive function, and TDP43 aggregation in adult neurons of VCPT262A-KI mice, whereas similar therapy in adulthood was less ef-fective. 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 cerebrospinalfluid (CSF) and serum of these patients. Collectively, developmental stress fol-lowed by early-stage neuronal necrosis is a potential target for therapeutics and one of the earliest general biomarkers for FTLD.
Original languageEnglish
Article numbere202101022
Number of pages23
JournalLife Science Alliance
Volume4
Issue number7
DOIs
Publication statusPublished - 1 Jul 2021

Keywords

  • VALOSIN-CONTAINING-PROTEIN
  • INCLUSION-BODY
  • REPAIR
  • DISEASE
  • COMPLEX
  • DEATH
  • TDP-43
  • GOLGI
  • PHOSPHORYLATION
  • PROLIFERATION

Cite this