RT Journal Article
SR Electronic
T1 DNA damage in embryonic neural stem cell determines FTLDs’ fate via early-stage neuronal necrosis
JF Life Science Alliance
JO Life Sci. Alliance
FD Life Science Alliance LLC
SP e202101022
DO 10.26508/lsa.202101022
VO 4
IS 7
A1 Hidenori Homma
A1 Hikari Tanaka
A1 Meihua Jin
A1 Xiaocen Jin
A1 Yong Huang
A1 Yuki Yoshioka
A1 Christian JF Bertens
A1 Kohei Tsumaki
A1 Kanoh Kondo
A1 Hiroki Shiwaku
A1 Kazuhiko Tagawa
A1 Hiroyasu Akatsu
A1 Naoki Atsuta
A1 Masahisa Katsuno
A1 Katsutoshi Furukawa
A1 Aiko Ishiki
A1 Masaaki Waragai
A1 Gaku Ohtomo
A1 Atsushi Iwata
A1 Takanori Yokota
A1 Haruhisa Inoue
A1 Hiroyuki Arai
A1 Gen Sobue
A1 Masaki Sone
A1 Kyota Fujita
A1 Hitoshi Okazawa
YR 2021
UL https://www.life-science-alliance.org/content/4/7/e202101022.abstract
AB 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.