Prediction and verification of the AD-FTLD common pathomechanism based on dynamic molecular network analysis

Meihua Jin,Hitoshi Okazawa,Hiroyasu Akatsu,Hidenori Homma,Kyota Fujita,Xiaocen Jin,Shigeo Murayama,Hikari Tanaka,Kazuhiko Tagawa

doi:10.1038/s42003-021-02475-6

Abstract

Multiple gene mutations cause familial frontotemporal lobar degeneration (FTLD) while no single gene mutations exists in sporadic FTLD. Various proteins aggregate in variable regions of the brain, leading to multiple pathological and clinical prototypes. The heterogeneity of FTLD could be one of the reasons preventing development of disease-modifying therapy. We newly develop a mathematical method to analyze chronological changes of PPI networks with sequential big data from comprehensive phosphoproteome of four FTLD knock-in (KI) mouse models (PGRNR504X-KI, TDP43N267S-KI, VCPT262A-KI and CHMP2BQ165X-KI mice) together with four transgenic mouse models of Alzheimer’s disease (AD) and with APPKM670/671NL-KI mice at multiple time points. The new method reveals the common core pathological network across FTLD and AD, which is shared by mouse models and human postmortem brains. Based on the prediction, we performed therapeutic intervention of the FTLD models, and confirmed amelioration of pathologies and symptoms of four FTLD mouse models by interruption of the core molecule HMGB1, verifying the new mathematical method to predict dynamic molecular networks.

Highlights

Multiple gene mutations cause familial frontotemporal lobar degeneration (FTLD) while no single gene mutations exists in sporadic FTLD
Employing frontotemporal lobar degeneration (FTLD) and Alzheimer’s disease (AD) as objects, we investigated a dynamic molecular network that is common across multiple dementias
We recently revealed that newly generated knockin mouse models carrying a gene mutation of TAR DNA-binding protein 43 (TDP43), PGRN, valosincontaining protein (VCP), or charged multivesicular body protein 2B (CHMP2B) at the conserved amino acid between mouse and human suffer DNA damage in embryonic neural stem cells owing to the loss of their DNA damage repair functions[39]

Summary

Introduction

Multiple gene mutations cause familial frontotemporal lobar degeneration (FTLD) while no single gene mutations exists in sporadic FTLD. The application to the research of neurodegenerative diseases has been limited to a few cases[3,4,5,6], and such research has not been performed to find a common pathology across different types of neurodegenerative diseases Another issue is that previous molecular network analyses have been static, i.e., performed only at a single time point. We recently revealed that newly generated knockin mouse models carrying a gene mutation of TDP43, PGRN, VCP, or CHMP2B at the conserved amino acid between mouse and human suffer DNA damage in embryonic neural stem cells owing to the loss of their DNA damage repair functions[39]. Interruption of HMGB1-TLR4 axis by anti-HMGB1 antibody ameliorates pathological progression and symptoms of AD model mice[41]

Methods

Results

Conclusion