Sadhukhan_2021_J.Inherit.Metab.Dis_44_1051

Reference

Title : In a mouse model of INCL reduced S-palmitoylation of cytosolic thioesterase APT1 contributes to microglia proliferation and neuroinflammation - Sadhukhan_2021_J.Inherit.Metab.Dis_44_1051
Author(s) : Sadhukhan T , Bagh MB , Appu AP , Mondal A , Zhang W , Liu A , Mukherjee AB
Ref : J Inherit Metab Dis , 44 :1051 , 2021
Abstract :

S-palmitoylation is a reversible posttranslational modification in which a 16-carbon saturated fatty acid (generally palmitate) is attached to specific cysteine residues in polypeptides via thioester linkage. Dynamic S-palmitoylation (palmitoylation-depalmitoylation), like phosphorylation-dephosphorylation, regulates the function of numerous proteins, especially in the brain. While a family of 23 palmitoyl-acyl transferases (PATS), commonly known as ZDHHCs, catalyze S-palmitoylation of proteins, the thioesterases, localized either in the cytoplasm (eg, APT1) or in the lysosome (eg, PPT1) mediate depalmitoylation. Previously, we reported that APT1 requires dynamic S-palmitoylation for shuttling between the cytosol and the plasma membrane. APT1 depalmitoylated H-Ras to regulate its signaling pathway that stimulates cell proliferation. Although we demonstrated that APT1 catalyzed its own depalmitoylation, the ZDHHC(s) that S-palmitoylated APT1 had remained unidentified. We report here that ZDHHC5 and ZDHHC23 catalyze APT1 S-palmitoylation. Intriguingly, lysosomal Ppt1-deficiency in Cln1(-/-) mouse, a reliable animal model of INCL, markedly reduced ZDHHC5 and ZDHHC23 levels. Remarkably, in the brain of these mice decreased ZDHHC5 and ZDHHC23 levels suppressed membrane-bound APT1, thereby, increasing plasma membrane-localized H-Ras, which activated its signaling pathway stimulating microglia proliferation. Increased inflammatory cytokines produced by microglia together with increased complement C1q level contributed to the transformation of astrocytes to neurotoxic A1 phenotype. Importantly, neuroinflammation was ameliorated by treatment of Cln1(-/-) mice with a PPT1-mimetic small molecule, N-tert(Butyl)hydroxylamine (NtBuHA). Our results revealed a novel pathway to neuropathology in an INCL mouse model and uncovered a previously unrecognized mechanism of the neuroprotective actions of NtBuHA and its potential as a drug target.

PubMedSearch : Sadhukhan_2021_J.Inherit.Metab.Dis_44_1051
PubMedID: 33739454
Gene_locus related to this paper: human-LYPLA1 , mouse-lypla1

Related information

Gene_locus human-LYPLA1    mouse-lypla1

Citations formats

Sadhukhan T, Bagh MB, Appu AP, Mondal A, Zhang W, Liu A, Mukherjee AB (2021)
In a mouse model of INCL reduced S-palmitoylation of cytosolic thioesterase APT1 contributes to microglia proliferation and neuroinflammation
J Inherit Metab Dis 44 :1051

Sadhukhan T, Bagh MB, Appu AP, Mondal A, Zhang W, Liu A, Mukherjee AB (2021)
J Inherit Metab Dis 44 :1051