La protéase rhomboide PARL, nouveau contrôleur de l'apoptose et de la régulation de la morphologie mitochondriale : découverte des mécanismes moléculaires reponsables de son activité

Tableau d'honneur de la Faculté des études supérieures et postdoctorales, 2006-200

Hax1 regulates neutrophil adhesion and motility through RhoA

Loss of Hax1, which is associated with a severe congenital neutropenia syndrome, impairs neutrophil uropod detachment and directed migration

Identification and Replication of Three Novel Myopia Common Susceptibility Gene Loci on Chromosome 3q26 using Linkage and Linkage Disequilibrium Mapping

Refractive error is a highly heritable quantitative trait responsible for considerable morbidity. Following an initial genome-wide linkage study using microsatellite markers, we confirmed evidence for linkage to chromosome 3q26 and then conducted fine-scale association mapping using high-resolution linkage disequilibrium unit (LDU) maps. We used a preliminary discovery marker set across the 30-Mb region with an average SNP density of 1 SNP/15 kb (Map 1). Map 1 was divided into 51 LDU windows and additional SNPs were genotyped for six regions (Map 2) that showed preliminary evidence of multi-marker association using composite likelihood. A total of 575 cases and controls selected from the tails of the trait distribution were genotyped for the discovery sample. Malecot model estimates indicate three loci with putative common functional variants centred on MFN1 (180,566 kb; 95% confidence interval 180,505–180, 655 kb), approximately 156 kb upstream from alternate-splicing SOX2OT (182,595 kb; 95% CI 182,533–182,688 kb) and PSARL (184,386 kb; 95% CI 184,356–184,411 kb), with the loci showing modest to strong evidence of association for the Map 2 discovery samples (p<10−7, p<10−10, and p = 0.01, respectively). Using an unselected independent sample of 1,430 individuals, results replicated for the MFN1 (p = 0.006), SOX2OT (p = 0.0002), and PSARL (p = 0.0005) gene regions. MFN1 and PSARL both interact with OPA1 to regulate mitochondrial fusion and the inhibition of mitochondrial-led apoptosis, respectively. That two mitochondrial regulatory processes in the retina are implicated in the aetiology of myopia is surprising and is likely to provide novel insight into the molecular genetic basis of common myopia

Mutations in PINK1 and Parkin Impair Ubiquitination of Mitofusins in Human Fibroblasts

PINK1 and Parkin mutations cause recessive Parkinson's disease (PD). In Drosophila and SH-SY5Y cells, Parkin is recruited by PINK1 to damaged mitochondria, where it ubiquitinates Mitofusins and consequently promotes mitochondrial fission and mitophagy

The Endoplasmic Reticulum Stress Response in Neuroprogressive Diseases: Emerging Pathophysiological Role and Translational Implications

The endoplasmic reticulum (ER) is the main cellular organelle involved in protein synthesis, assembly and secretion. Accumulating evidence shows that across several neurodegenerative and neuroprogressive diseases, ER stress ensues, which is accompanied by over-activation of the unfolded protein response (UPR). Although the UPR could initially serve adaptive purposes in conditions associated with higher cellular demands and after exposure to a range of pathophysiological insults, over time the UPR may become detrimental, thus contributing to neuroprogression. Herein, we propose that immune-inflammatory, neuro-oxidative, neuro-nitrosative, as well as mitochondrial pathways may reciprocally interact with aberrations in UPR pathways. Furthermore, ER stress may contribute to a deregulation in calcium homoeostasis. The common denominator of these pathways is a decrease in neuronal resilience, synaptic dysfunction and even cell death. This review also discusses how mechanisms related to ER stress could be explored as a source for novel therapeutic targets for neurodegenerative and neuroprogressive diseases. The design of randomised controlled trials testing compounds that target aberrant UPR-related pathways within the emerging framework of precision psychiatry is warranted

Structural and mechanistic basis of the activity and regulation of the mitochondrial rhomboid protease parl

Le travail présenté dans cette étude a été réalisé au laboratoire du Dr. Luca Pellegrini, qui se concentre sur les mécanismes régulant la dynamique mitochondriale. Dans ce contexte, mon travail s'est focalisé sur la protease rhomboïde Parl, un régulateur essentiel de l'apoptose, de la morphologie mitochondriale et du métabolisme et qui a été impliquée dans la maladie de Parkinson. Au cours de ce travail, nous avons adopté une approche en deux points pour comprendre les bases structurelles et mécanistiques de l'activité protéolytique de Pari et de sa régulation. Dans une première approche, nous avons réalisé une analyse de la structurefonction basée sur un modèle d'homologie pour identifier les déterminants structurels de Pari. L'identification d'un événement de coupure protéique (clivage- Y) qui génère une nouvelle forme de Pari présentant une structure à six segments transmembranaires à partir de la structure classique à 6+1 segments transmembranaires nous a servi de base pour cette étude. Nos résultats montrent des similarités de structure entre la protéine rhomboïde d'origine bactérienne GlpG and Pari. Cependant, Pari semble utiliser une catalyse par triade par opposition à la catalyse par dyade opérée par les rhomboïdes GlpG. Le clivage y perturbe la triade et rend ainsi Pari protéolytiquement inactif. Ainsi, notre étude a identifiée la régulation de la fonction de Pari par l'élimination protéolytique de son activité, ce que nous avons publié dans le journal Cell Death & Differentiation. Dans une seconde approche, nous nous sommes penché sur la validité d'un communiqué publié dans Nature (Chao et al., 2008) qui suppose un rôle pour la protéine HAX1 en tant que protéine présentatrice de substrat pour Pari. En effet, plusieurs faisceaux de preuves n'étaient pas cohérents avec les résultats de cette étude. Nos résultats montrent que Pari et HAX1 sont confinés dans des souscompartiments cellulaires distincts et que l'interaction observée in vitro n'est qu'un artefact. Ainsi in vivo, HAX1 ne peut pas contribuer à la régulation de la protéolyse 2opérée par Pari. Notre étude a contesté les résultats de Chao et al., et a été publiée dans un article de fond dans le journal Cell Death & Differentiation. Enfin, il est important de mentionner qu'au cours de mon doctorat j'ai été le coauteur d'une revue (Jeyaraju et al., BBA 2009) et de deux articles de recherche à travers des collaborations avec les laboratoires du Dr Toth (Lavoie et al., J.Neuroscience, 2011 ) et du Dr Shore (Warr et al., JBC, 2011 )

Embryonal Rhabdomyosarcoma with Posttherapy Cytodifferentiation and Aggressive Clinical Course

Rhabdomyosarcoma is the most common soft tissue sarcoma in children and adolescents. Embryonal rhabdomyosarcoma (ERMS), its most common subtype, is a malignant soft tissue tumor with morphologic and immunophenotypic features of embryonic skeletal muscle. The histologic findings in ERMS typically include a range of differentiation in rhabdomyoblasts from primitive to terminally differentiated forms, and the latter become more prominent after chemotherapy-induced cytodifferentiation. Several reports have shown therapy-related cytodifferentiation to portend a good prognosis in ERMS. We discuss the case of a pediatric patient who presented with ERMS of the orbit. Although her tumor showed extensive posttreatment cytodifferentiation and several other good prognostic clinicopathologic factors, it pursued an aggressive course, resulting in early metastasis and death. This case represents an unusual course and may be instructive as to the clinicopathologic features impacting prognostication, and ultimately the biology, of this aggressive family of tumors