Exome sequencing revealed PDE11A as a novel candidate gene for early-onset Alzheimer’s disease

Abstract

To identify novel risk genes and better understand the molecular pathway underlying Alzheimer’s disease (ad), whole-exome sequencing (WES) 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 cAMP levels, protein kinase A (PKA) activation, and cAMP response element-binding protein (CREB) phosphorylation. Additionally, 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.

Conserved age‐related increases in hippocampal PDE11A4 cause unexpected proteinopathies and cognitive decline of social associative memories

“…This is particularly interesting given that pathway analysis of our previous proteomics study of VHIPP from Pde11a KO versus WT mice (Pilarzyk et al, 2021 ), along with pathway analyses of the RNA sequencing and phosphoproteomics studies reported herein (Table 2 ), identified the Alzheimer's disease pathway. Together, our findings complement those of Qin and colleagues who associated rare PDE11A mutations with early‐onset Alzheimer's Disease (Qin et al, 2021 ). The TBI‐associated dementia‐related increase in PDE expression is unique to PDE11A in that PDE2A, PDE5A, and PDE10A expression remained unchanged.…”

Genetic and Multi-omic Risk Assessment of Alzheimer’s Disease Implicates Core Associated Biological Domains

“…Genetic Considerations in Selecting Biological Domains. In genetics, we focused on key genome wide GWAS, the newer genome wide association study by proxy (GWAX) [15][16][17][18][19][36][37][38][39][40][41][42] using the parental disease status, and whole exome sequencing studies [43][44][45][46][47][48][49][50][51][52][53][54][55][56][57] that have transpired over the last decade. The identi cation of potential genetic risk associated with individual genes is represented in the genetics score (detailed below), and the goal here is not to recapitulate the scoring methodology, but to assess the potential biological contexts of the imputed genes' biological function.…”

Genetic and Multi-omic Risk Assessment of Alzheimer’s Disease Implicates Core Associated Biological Domains

“…Genetic Considerations in Selecting Biological Domains. In genetics, we focused on key genome wide association studies (GWAS), the newer genome wide association study by proxy (GWAX) [15][16][17][18][19][74][75][76][77][78][79][80] using the parental disease status, and whole exome sequencing studies [81][82][83][84][85][86][87][88][89][90][91][92][93][94][95] that have transpired over the last decade. The identification of potential genetic risk associated with individual genes is represented in the genetics score (detailed below), and the goal here is not to recapitulate the scoring methodology, but to assess the potential biological contexts of the imputed genes' biological function.…”