Akap5 links synaptic dysfunction to neuroinflammatory signaling in a mouse model of infantile neuronal ceroid lipofuscinosis

• DOI: 10.3389/fnsyn.2024.1384625
• Publication Date: 2024-05-10T05:10:06Z
• Authors: Kevin P. Koster; Zach Fyke; Thu T. A. Nguyen; Amanda Niqula; Lorena Y. Noriega...; Kevin M. Woolfrey; Mark L. Dell’Acqua; Stephanie M. Cologna; Akira Yoshii
• Keywords: NFAT; Palmitoylation

Palmitoylation and depalmitoylation represent dichotomic processes by which a labile posttranslational lipid modification regulates protein trafficking degradation. The depalmitoylating enzyme, palmitoyl-protein thioesterase 1 (PPT1), is associated with the devastating pediatric neurodegenerative condition, infantile neuronal ceroid lipofuscinosis (CLN1). CLN1 characterized accumulation of autofluorescent lysosomal storage material (AFSM) in neurons robust neuroinflammation. Converging lines evidence suggest that addition to cellular waste accumulation, symptomology corresponds disruption synaptic processes. Indeed, loss Ppt1 function cortical dysregulates incorporation GluA1 AMPA receptor (AMPAR) subunit during type plasticity called scaling. However, mechanisms causing this aberration are unknown. Here, we used −/− mouse model (both sexes) further investigate how its affects downstream signaling pathways. To end, performed palmitoyl-proteomic screen, provoked discovery Akap5 excessively palmitoylated at synapses. Extending our previous data, vivo induction scaling, regulated Akap5, caused an excessive upregulation mice. This change was exacerbated disease pathology. Furthermore, Akap5- inflammation-associated transcriptional regulator, nuclear factor activated T cells (NFAT), sensitized neurons. Suppressing upstream regulator NFAT activation, calcineurin, FDA-approved therapeutic FK506 (Tacrolimus) modestly improved neuroinflammation These findings indicate absence stifles contributes via Akap5-associated mechanism.