TY - JOUR
T1 - Exome sequencing revealed PDE11A as a novel candidate gene for early-onset Alzheimer's disease
AU - Qin, Wei
AU - Zhou, Aihong
AU - Zuo, Xiumei
AU - Jia, Longfei
AU - Li, Fangyu
AU - Wang, Qi
AU - Li, Ying
AU - Wei, Yiping
AU - Jin, Hongmei
AU - Cruchaga, Carlos
AU - Benitez, Bruno A.
AU - Jia, Jianping
N1 - Publisher Copyright:
© 2021 The Author(s) 2021. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected].
PY - 2021/5/1
Y1 - 2021/5/1
N2 - To identify novel risk genes and better understand the molecular pathway underlying Alzheimer's disease (AD), whole-exome sequencing was performed in 215 early-onset AD (EOAD) patients and 255 unrelated healthy controls of Han Chinese ethnicity. Subsequent validation, computational annotation and in vitro functional studies were performed to evaluate the role of candidate variants in EOAD. We identified two rare missense variants in the phosphodiesterase 11A (PDE11A) gene in individuals with EOAD. Both variants are located in evolutionarily highly conserved amino acids, are predicted to alter the protein conformation and are classified as pathogenic. Furthermore, we found significantly decreased protein levels of PDE11A in brain samples of AD patients. Expression of PDE11A variants and knockdown experiments with specific short hairpin RNA (shRNA) for PDE11A both resulted in an increase of AD-associated Tau hyperphosphorylation at multiple epitopes in vitro. PDE11A variants or PDE11A shRNA also caused increased cyclic adenosine monophosphate (cAMP) levels, protein kinase A (PKA) activation and cAMP response element-binding protein phosphorylation. In addition, pretreatment with a PKA inhibitor (H89) suppressed PDE11A variant-induced Tau phosphorylation formation. This study offers insight into the involvement of Tau phosphorylation via the cAMP/PKA pathway in EOAD pathogenesis and provides a potential new target for intervention.
AB - To identify novel risk genes and better understand the molecular pathway underlying Alzheimer's disease (AD), whole-exome sequencing was performed in 215 early-onset AD (EOAD) patients and 255 unrelated healthy controls of Han Chinese ethnicity. Subsequent validation, computational annotation and in vitro functional studies were performed to evaluate the role of candidate variants in EOAD. We identified two rare missense variants in the phosphodiesterase 11A (PDE11A) gene in individuals with EOAD. Both variants are located in evolutionarily highly conserved amino acids, are predicted to alter the protein conformation and are classified as pathogenic. Furthermore, we found significantly decreased protein levels of PDE11A in brain samples of AD patients. Expression of PDE11A variants and knockdown experiments with specific short hairpin RNA (shRNA) for PDE11A both resulted in an increase of AD-associated Tau hyperphosphorylation at multiple epitopes in vitro. PDE11A variants or PDE11A shRNA also caused increased cyclic adenosine monophosphate (cAMP) levels, protein kinase A (PKA) activation and cAMP response element-binding protein phosphorylation. In addition, pretreatment with a PKA inhibitor (H89) suppressed PDE11A variant-induced Tau phosphorylation formation. This study offers insight into the involvement of Tau phosphorylation via the cAMP/PKA pathway in EOAD pathogenesis and provides a potential new target for intervention.
UR - http://www.scopus.com/inward/record.url?scp=85107163319&partnerID=8YFLogxK
U2 - 10.1093/hmg/ddab090
DO - 10.1093/hmg/ddab090
M3 - Article
C2 - 33835157
AN - SCOPUS:85107163319
SN - 0964-6906
VL - 30
SP - 811
EP - 822
JO - Human molecular genetics
JF - Human molecular genetics
IS - 9
ER -