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

• Published in: Life science alliance 2021-07, Vol.4 (7), p.e202101022
• Main Authors: Homma, Hidenori, Tanaka, Hikari, Jin, Meihua, Jin, Xiaocen, Huang, Yong, Yoshioka, Yuki, Bertens, Christian JF, Tsumaki, Kohei, Kondo, Kanoh, Shiwaku, Hiroki, Tagawa, Kazuhiko, Akatsu, Hiroyasu, Atsuta, Naoki, Katsuno, Masahisa, Furukawa, Katsutoshi, Ishiki, Aiko, Waragai, Masaaki, Ohtomo, Gaku, Iwata, Atsushi, Yokota, Takanori, Inoue, Haruhisa, Arai, Hiroyuki, Sobue, Gen, Sone, Masaki, Fujita, Kyota, Okazawa, Hitoshi
• Format: Article
• Language: English
• ISSN: 2575-1077; 2575-1077
• DOI: 10.26508/lsa.202101022

The early-stage pathologies of frontotemporal lobal degeneration (FTLD) remain largely unknown. In VCP T262A -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 VCP T262A -KI mice, whereas similar therapy in adulthood was less effective. The similar early-stage neuronal necrosis was detected in PGRN R504X -KI, CHMP2B Q165X -KI, and TDP N267S -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.