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.
Highlights
Frontotemporal lobar degeneration (FTLD) is the third largest group of neurodegenerative dementia following Alzheimer’s disease (AD)and Lewy body dementia
The primary significance of this study is the discovery that developmental stress due to DNA damage response (DDR) triggered by accumulation of unrepaired DNA damage in neural stem/progenitor cells (NSCs) contributes to initiation of the ultra-early stage FTLD pathology
In VCPT262A-KI mice, DNA repair in embryonic NSCs led to accumulation of DNA damage, DDR activation, maintenance complex component 3 (MCM3) phosphorylation, partial G1/S arrest, excessive neurogenesis, depletion of the NSC pool, abnormal layer structure, and sustained DNA damage in neurons linked to early-stage neuronal necrosis (Fig S18)
Summary
Frontotemporal lobar degeneration (FTLD) is the third largest group of neurodegenerative dementia following Alzheimer’s disease (AD)and Lewy body dementia. The largest group is FTLD with aggregation of TDP43 (transactive response [TAR] DNA-binding protein of 43 kD), called FTLD-TDP. Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia with FTLD-TDP (Watts et al, 2004; Schroder et al, 2005) is caused by valosin containing protein (VCP) mutations. VCP contributes to DNA double-strand break (DSB) repair by non-homologous end joining (NHEJ) (Acs et al, 2011; Meerang et al, 2011; Fujita et al, 2013; van den Boom et al, 2016) in nonproliferating cells. Recent work showed that VCP regulates homologous recombination (Meerang et al, 2011; Bergink et al, 2013; van den Boom et al, 2016; Torrecilla et al, 2017), another DSB repair mechanism active in proliferating cells
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