Rapp, S. | bioRxiv Science

bioRxiv2024

Autophagosomes coordinate an AKAP11-dependent regulatory checkpoint that shapes neuronal PKA signaling

Protein Kinase A (PKA) is regulated spatially and temporally via scaffolding of its catalytic (C/{beta}) and regulatory (RI/RII) subunits by the A-kinase-anchoring proteins (AKAP). PKA engages in poorly understood interactions with autophagy, a key degradation pathway for neuronal cell homeostasis, partly via its AKAP11 scaffold. Mutations in AKAP11 drive schizophrenia and bipolar disorders (SZ-BP) through unknown mechanisms. Through proteomic-based analysis of immunopurified lysosomes, we identify the C-RI-AKAP11 holocomplex as a prominent autophagy-associated protein kinase complex. AKAP11 scaffolds C-RI to the autophagic machinery via its LC3-interacting region (LIR), enabling both PKA regulation by upstream signals, and its autophagy-dependent degradation. We identify Ser83 on the RI linker-hinge region as an AKAP11-dependent phospho-residue that modulates RI-C binding and cAMP-induced PKA activation. Decoupling AKAP11-PKA from autophagy alters Ser83 phosphorylation, supporting an autophagy-dependent checkpoint for PKA signaling. Ablating AKAP11 in induced pluripotent stem cell-derived neurons reveals dysregulation of multiple pathways for neuronal homeostasis. Thus, the autophagosome is a novel platform that modulate PKA signaling, providing a possible mechanistic link to SZ/BP pathophysiology.

cell biology↗

bioRxiv2021

Association between Cognitive Function and Large Optic Nerve Cupping, Accounting for Cup-Disc-Ratio Genetic Risk Score

PurposeTo investigate if accounting for a cup-to-disc ratio (CDR) genetic risk score (GRS) modified the association between large CDR and cognitive function among women. DesignThis was a retrospective study using data from the Womens Health Initiative. MethodsPatients with glaucoma or ocular hypertension were excluded. Large CDR was defined as [≥] 0.6 in either eye. Cognitive function was measured by the Modified Mini-Mental State Examination (3MSE). We used the combined effects from 13 single nucleotide polymorphisms (SNPs) to formulate the GRS for CDR. We used logistic regression to investigate associations between weighted GRS and large CDR, then a linear regression to assess the association between weighted GRS and 3MSE scores, and between weighted GRS, CDR, and 3MSE scores, adjusted for demographic and clinical characteristics. ResultsFinal analyses included 1,196 White women with mean age of 69.60 {+/-} 3.62 years and 7.27% with large CDR. Mean GRS in women with and without large CDR was 1.51 {+/-} 0.31 vs. 1.41 {+/-} 0.36, respectively (p = 0.004). The odds of large CDR for a one unit increase in GRS was 2.30 (95% CI: (1.22, 4.36), p = 0.011). Adding the CDR GRS in the model with CDR and 3MSE, women with large CDR still had statistically significantly lower 3MSE scores than those without large CDR, yielding a predicted mean difference in 3MSE scores of 0.84 (p = 0.007). ConclusionsIndependent of the CDR GRS, women with large CDR had a lower cognitive function.

genetics↗