Decrease of neuronal FKBP4/FKBP52 modulates perinuclear lysosomal positioning and MAPT/Tau behavior during MAPT/Tau-induced proteotoxic stress.

ABSTRACT

Defects of autophagy-lysosomal protein degradation are thought to contribute to the pathogenesis of several neurodegenerative diseases, and the accumulation of aggregation prone proteins such as MAPT/Tau in Alzheimer disease (AD). We previously showed the localization of the immunophilin FKBP4/FKBP52 in the lysosomal system of healthy human neurons suggesting its possible role in lysosome function. We also showed that decreased FKBP4 levels in AD brain neurons correlate with abnormal MAPT accumulation and aggregation. In this study, we demonstrate that FKBP4 decrease in a human neuronal cell line (SH-SY5Y) and in dorsal root ganglion (DRG) neurons from human MAPTP301S transgenic mice affected the function of the autophagy-lysosomal system under MAPT induced proteotoxic stress conditions. We show that acute MAPT accumulation in SH-SY5Y cells induced perinuclear clustering of lysosomes, triggered FKBP4 localization around the clusters and its colocalization with MAPT and MAP1LC3/LC3-positive autophagic vesicles; a similar FKBP4 localization was detected in some AD brain neurons. We demonstrate that FKBP4 decrease altered lysosomal clustering along with MAPT and MAP1LC3 secretion increase. Although ectopic FKBP4 expression could not induce autophagy under our experimental conditions, it prevented MAPT secretion after MAPT accumulation in SH-SY5Y cells implying a regulatory role of FKBP4 on MAPT secretion. Finally, we observe that FKBP4 deficiency decreased MAP1LC3-II expression and provoked MAPT accumulation during long-term stress in mouse DRG neurons. We hypothesize that the abnormal FKBP4 decrease observed in AD brain neurons might hinder autophagy efficiency and contribute to the progression of the tauopathy by modulating MAPT secretion and accumulation during MAPT pathogenesis.Abbreviations AD Alzheimer disease; AKT/protein kinase B AKT serine/threonine kinase; ALP Autophagy-lysosomal pathway; ATG autophagy-related; BafA1 bafilomycin A1; CQ chloroquine; CTSD cathepsin D; DIV days in vitro; DRG dorsal root ganglion neurons; Dox doxycycline; DNAJC5 DnaJ heat shock protein family (Hsp40) member C5; EL empty lentiviral vectors; ENO2/NSE enolase 2, gamma neuronal; FKBP4/FKBP52 FKBP prolyl isomerase 4; FTLD-Tau frontotemporal lobar degeneration with Tau pathology; GFP green fluorescent protein; LAMP1 lysosomal associated membrane protein 1; LDH lactate dehydrogenase; MAP1LC3/LC3 microtubule associated protein 1 light chain 3; MAPT/Tau microtubule associated protein tau; MTT tetrazolium salt; NFTs neurofibrillary tangles; RPE-1 retinal pigment epithelial cells; shRNA small-hairpin ribonucleic acid; SQSTM1/p62 sequestosome 1; SD standard deviation; SEM standard error of the mean; SH-SY5Y human neuroblastoma cells; Sh1 or Sh2 Lentiviral shRNA vectors inducing FKBP4 decrease; SH-52GFP MAPT/Tau-inducible SH-SY5Y cell line constitutively expressing FKBP4-GFP; TUBB3/ßIII tubulin tubulin beta 3 class III; UPS ubiquitin-proteasome system.