The Transcription Factor Function of Parkin: Breaking the Dogma

PRKN (PARK2) is a key gene involved in both familial and sporadic Parkinson’s disease that encodes parkin (PK). Since its discovery by the end of the 90s, both functional and more recently, structural studies led to a consensual view of PK as an E3 ligase only. It is generally considered that this function conditions the cellular load of a subset of cytosolic proteins prone to proteasomal degradation and that a loss of E3 ligase function triggers an accumulation of potentially toxic substrates and, consequently, a neuronal loss. Furthermore, PK molecular interplay with PTEN-induced kinase 1 (PINK1), a serine threonine kinase also involved in recessive cases of Parkinson’s disease, is considered to underlie the mitophagy process. Thus, since mitochondrial homeostasis significantly governs cell health, there is a huge interest of the scientific community centered on PK function. In 2009, we have demonstrated that PK could also act as a transcription factor (TF) and induces neuroprotection via the downregulation of the pro-apoptotic and tumor suppressor factor, p53. Importantly, the DNA-binding properties of PK and its nuclear localization suggested an important role in the control of several genes. The duality of PK subcellular localization and of its associated ubiquitin ligase and TF functions suggests that PK could behave as a key molecular modulator of various physiological cellular signaling pathways that could be disrupted in pathological contexts. Here, we update the current knowledge on PK direct and indirect TF-mediated control of gene expression

The transcription factor EB reduces the intraneuronal accumulation of the beta-secretase-derived APP fragment C99 in cellular and mouse Alzheimer’s disease models

Brains that are affected by Alzheimer’s disease (AD) are characterized by the overload of extracellular amyloid β (Aβ) peptides, but recent data from cellular and animal models propose that Aβ deposition is preceded by intraneuronal accumulation of the direct precursor of Aβ, C99. These studies indicate that C99 accumulation firstly occurs within endosomal and lysosomal compartments and that it contributes to early-stage AD-related endosomal-lysosomal-autophagic defects. Our previous work also suggests that C99 accumulation itself could be a consequence of defective lysosomal-autophagic degradation. Thus, in the present study, we analyzed the influence of the overexpression of the transcription factor EB (TFEB), a master regulator of autophagy and lysosome biogenesis, on C99 accumulation occurring in both AD cellular models and in the triple-transgenic mouse model (3xTgAD). In the in vivo experiments, TFEB overexpression was induced via adeno-associated viruses (AAVs), which were injected either into the cerebral ventricles of newborn mice or administrated at later stages (3 months of age) by stereotaxic injection into the subiculum. In both cells and the 3xTgAD mouse model, exogenous TFEB strongly reduced C99 load and concomitantly increased the levels of many lysosomal and autophagic proteins, including cathepsins, key proteases involved in C99 degradation. Our data indicate that TFEB activation is a relevant strategy to prevent the accumulation of this early neurotoxic catabolite

Tissue- and sex-specific small RNAomes reveal sex differences in response to the environment.

RNA interference (RNAi) related pathways are essential for germline development and fertility in metazoa and can contribute to inter- and trans-generational inheritance. In the nematode Caenorhabditis elegans, environmental double-stranded RNA provided by feeding can lead to heritable changes in phenotype and gene expression. Notably, transmission efficiency differs between the male and female germline, yet the underlying mechanisms remain elusive. Here we use high-throughput sequencing of dissected gonads to quantify sex-specific endogenous piRNAs, miRNAs and siRNAs in the C. elegans germline and the somatic gonad. We identify genes with exceptionally high levels of secondary 22G RNAs that are associated with low mRNA expression, a signature compatible with silencing. We further demonstrate that contrary to the hermaphrodite germline, the male germline, but not male soma, is resistant to environmental RNAi triggers provided by feeding, in line with previous work. This sex-difference in silencing efficacy is associated with lower levels of gonadal RNAi amplification products. Moreover, this tissue- and sex-specific RNAi resistance is regulated by the germline, since mutant males with a feminized germline are RNAi sensitive. This study provides important sex- and tissue-specific expression data of miRNA, piRNA and siRNA as well as mechanistic insights into sex-differences of gene regulation in response to environmental cues.This work was funded by grants from the Swiss National Science Foundation and an advanced European Research Council grant to Laurent Keller, grants from Cancer Research UK (C13474/A18583, C6946/A14492) and the Wellcome Trust (104640/ Z/14/Z, 092096/Z/10/Z) to Eric A. Miska, and grants from the National Institutes of Health to Sean M. West (NIGMSNHRA 5F32GM100614) and to Fabio Piano and Kristin Gunsalus (NHGRI U01 HG004276, NICHD R01 HD046236), and by research funding from New York University Abu Dhabi to Fabio Piano and Kristin Gunsalus

Transcription- and phosphorylation-dependent control of a functional interplay between XBP1s and PINK1 governs mitophagy and potentially impacts Parkinson disease pathophysiology

© 2021 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way.Parkinson disease (PD)-affected brains show consistent endoplasmic reticulum (ER) stress and mitophagic dysfunctions. The mechanisms underlying these perturbations and how they are directly linked remain a matter of questions. XBP1 is a transcription factor activated upon ER stress after unconventional splicing by the nuclease ERN1/IREα thereby yielding XBP1s, whereas PINK1 is a kinase considered as the sensor of mitochondrial physiology and a master gatekeeper of mitophagy process. We showed that XBP1s transactivates PINK1 in human cells, primary cultured neurons and mice brain, and triggered a pro-mitophagic phenotype that was fully dependent of endogenous PINK1. We also unraveled a PINK1-dependent phosphorylation of XBP1s that conditioned its nuclear localization and thereby, governed its transcriptional activity. PINK1-induced XBP1s phosphorylation occurred at residues reminiscent of, and correlated to, those phosphorylated in substantia nigra of sporadic PD-affected brains. Overall, our study delineated a functional loop between XBP1s and PINK1 governing mitophagy that was disrupted in PD condition.Abbreviations: 6OHDA: 6-hydroxydopamine; baf: bafilomycin A1; BECN1: beclin 1; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; CASP3: caspase 3; CCCP: carbonyl cyanide chlorophenylhydrazone; COX8A: cytochrome c oxidase subunit 8A; DDIT3/CHOP: DNA damage inducible transcript 3; EGFP: enhanced green fluorescent protein; ER: endoplasmic reticulum; ERN1/IRE1α: endoplasmic reticulum to nucleus signaling 1; FACS: fluorescence-activated cell sorting; HSPD1/HSP60: heat shock protein family D (Hsp60) member 1; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MFN2: mitofusin 2; OPTN: optineurin; PD: Parkinson disease; PINK1: PTEN-induced kinase 1; PCR: polymerase chain reaction:; PRKN: parkin RBR E3 ubiquitin protein ligase; XBP1s [p-S61A]: XBP1s phosphorylated at serine 61; XBP1s [p-T48A]: XBP1s phosphorylated at threonine 48; shRNA: short hairpin RNA, SQSTM1/p62: sequestosome 1; TIMM23: translocase of inner mitochondrial membrane 23; TM: tunicamycin; TMRM: tetramethyl rhodamine methylester; TOMM20: translocase of outer mitochondrial membrane 20; Toy: toyocamycin; TP: thapsigargin; UB: ubiquitin; UB (S65): ubiquitin phosphorylated at serine 65; UPR: unfolded protein response, XBP1: X-box binding protein 1; XBP1s: spliced X-box binding protein 1.info:eu-repo/semantics/publishedVersio

Propriétés et régulation des prolyl-4-hydroxylases impliquées dans l'adaptation hypoxique des cellules

The prolyl-4-hydroxylases (PHD) are oxygen sensors that measure oxygen fluctuations in cells. Under normoxia they hydroxylate two prolines within the ODD domain of the hypoxia transcription factor HIF-1a. These hydroxylated prolines bind to the von Hippel Lindau (VHL) protein and target HIF-1a to the proteasome. Under hypoxia PHD are inactive: HIF-1a accumulates, binds to HIF-1b and induces the transcription of hypoxia sensitive genes. This thesis is a contribution to the analysis of biochemical and pharmacological proprieties of PHD. We have shown that : in vitro: cyclosporin A stimulated PHD activity and inhibited the hypoxic stabilization of HIF-1a; by this mechanism it reduced the hypoxic tolerance ; hypoxia induced PHD expression ; reoxygenation stimulated PHD activity and induced a rapid degradation of HIF-1a / in vivo in drosophila: the proline 850 in the ODD domain of Similar (the HIF-1a homologue) was a PHD target ; its hydroxylation allowed VHL binding ; the hypoxic signalling pathway, conserved in the trachea, was tissue specific. The PHDs play a key role in the hypoxic stabilization of ODD-containing proteins and in hypoxic adaptation of cells. The PHDs are potential pharmacological and therapeutic targets for the treatment of ischemic pathologies.Les prolyl-4-hydroxylases (PHD) sont des capteurs d'oxygène qui mesurent les variations de la pression partielle en oxygène dans les cellules. En normoxie elles hydroxylent deux prolines du domaine ODD du facteur transcription hypoxique HIF-1 Les prolines hydroxylées fixent la protéine von Hippel Lindau (VHL) et cible HIF-1 vers le protéasome. En hypoxie, les PHD sont inactives : HIF-1 s'accumule, s'associe à HIF-1 et induit la transcription des gènes impliqués dans l'adaptation hypoxique. Cette thèse est une contribution à l'analyse des propriétés biochimiques et pharmacologiques des PHD. Nous avons montré que : In vitro : la cyclosporine A, en activant les PHD, inhibe la stabilisation hypoxique de HIF-1, Par ce mécanisme elle réduit la tolérance hypoxique ; l'hypoxie induit l'expression de PHD ; la réoxygénation stimule l'activité des PHD et induit une dégradation rapide de HIF-1 . Ce rétrocontrôle négatif de HIF-1 limite les effets de l'hypoxie In vivo chez la drosophile ; la proline 850 du domaine ODD de Similar (l'homologue de HIF-1 ) est la cible de la PHD ; son hydroxylation permet la fixation de VHL ; la voie de signalisation hypoxique, conservée dans les trachées, présente une spécificité tissulaire. Les PHD jouent un rôle clef dans la stabilisation hypoxique de protéines à domaine ODD et dans l'adaptation hypoxique des cellules. Ce sont des cibles pharmacologiques et thérapeutiques potentielles pour le traitement des pathologies ischémiques.NICE-BU Sciences (060882101) / SudocSudocFranceF

The Transcription Factor XBP1 in Memory and Cognition: implications in Alzheimer’s Disease

Abstract X-box binding protein 1 (XBP1) is a unique basic region leucine zipper transcription factor that was isolated two decades ago in a search for regulators of major histocompatibility complex class II gene expression. XBP1 is a very complex protein that regulates many physiological functions, including the immune system, inflammatory responses and lipid metabolism. Evidence over the past few years suggests that XBP1 also plays an important role in pathological settings, since its activity as a transcription factor has profound effects on the prognosis and progression of diseases such as cancer, neurodegeneration and diabetes. Here we provide an overview of recent advances in our understanding of this multifaceted molecule, particularly in regulating synaptic plasticity and memory function, and the implications in neurodegenerative diseases, with an emphasis on Alzheimer’s disease