Travaux récemment publiés

Production d'organoïdes mésencéphaliques humains

En collaboration avec l'équipe du Dr. Durcan, nous avons développé un protocole pour différencier avec succès des cellules souches pluripotentes induites humaines en organoïdes mésencéphaliques en 3 dimensions

 

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Investiguer la complexe composition des VDMs

Les vésicules dérivées des mitochondries (VDMs) sont impliquées dans le contrôle qualité mitochondrial, mécanisme potentiellement important pour la MP. La diversité et la composition des VDMs sont encore très peu connues. Notre étude vise à déterminer la composition des VDMs dans le cerveau.

 

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Explorer le paysage des variants de Parkin

Les mutations dans la protéine Parkin sont souvent associées au développement précoce de la MP, mais de nombreux variants existent. Dans cette étude, nous avons développé un procédé pour classifier les variants de Parkin selon leur pathogénicité, en se basant sur l'intégration de données cliniques et fonctionnelles.

 

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Approfondir notre compréhension des mutations de SMPD1

Les variants de la sphingomyélinase (SMPD1) ont été associés à la maladie de Parkinson. Dans cette étude collaborative, les mutations de SMPD1 ont été caractérisées par diverses approches: génétique, protéomique et cellulaire

 

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Explorer la fonction des sites de contact  mitochondries-RE

Les sites de contact mitochondries-RE sont très peu étudiés. Ici nous investiguons leur rôle dans les mécanismes de contrôle de la qualité mitochondriale

 

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Publications

Publications sélectionnées 

Del Cid-Pellitero E, Tavassoly O, Larroquette F, Cai E, Thomas RA, Soubannier V, Luo W, Durcan TM, Fon EA. Pharmacological Inhibition of Brain EGFR Activation By a BBB-penetrating Inhibitor, AZD3759, Attenuates α-synuclein Pathology in a Mouse Model of α-Synuclein Propagation. Neurotherapeutics 2021 [Lire l’article]


Del Cid-Pellitero E, Jin JW, Fan X, Liu XX, Zhou L, Dai C, Gibbs E, He W, Li H, Wu X, Hill A, Leavitt BR, Cashman N, Liu L, Lu J, Durcan TM, Dong Z, Fon EA & Wang YT. Development of an α-synuclein knockdown peptide and evaluation of its efficacy in Parkinson’s disease models. Communications Biology 2021 [Lire l’article]


Roberts R., Bayne AN., Goiran T., Lévesque D., Boisvert FM., Trempe JF., Fon EA. Proteomic Profiling of Mitochondrial-Derived Vesicles in Brain Reveals Enrichment of Respiratory Complex Sub-assemblies and Small TIM Chaperones. J Proteome Res  2021 [Lire l’article]


Jefri M, Bell S, Peng H, Hettige N, Maussion G, Soubannier V, Wu H, Silveira H, Theroux JF, Moquin L, Zhang X, Aouabed Z, Krishnan J, O'Leary LA, Antonyan L, Zhang Y, McCarty V, Mechawar N, Gratton A, Schuppert A, Durcan TM, Fon EA, Ernst C. Stimulation of L-type calcium channels increases tyrosine hydroxylase and dopamine in ventral midbrain cells induced from somatic cells. Stem Cells Transl Med. 2020 [Lire l’article]


Martínez GF, Gazal NG, Quassollo G, Szalai AM, Cid-Pellitero ED, Durcan TM, Fon EA, Bisbal M, Stefani FD, Unsain N. Quantitative expansion microscopy for the characterization of the spectrin periodic skeleton of axons using fluorescence microscopy. Sci. Rep. 2020;10(1):2917. [Lire l’article]


Gan-Or Z, Rao T, Leveille E, Degroot C, Chouinard S, Cicchetti F, Dagher A, Das S, Desautels A, Drouin-Ouellet J, Durcan T, Gagnon JF, Genge A, Karamchandani J, Lafontaine AL, Sun SLW, Langlois M, Levesque M, Melmed C, Panisset M, Parent M, Poline JB, Postuma RB, Pourcher E, Rouleau GA, Sharp M, Monchi O, Dupré N, Fon EA. The Quebec Parkinson Network: A Researcher-Patient Matching Platform and Multimodal Biorepository. J Parkinsons Dis. 2020;10(1):301-313 [Lire l’article]


Eldeeb MA, MacDougall EJ, Ragheb MA, Fon EA. Beyond ER: Regulating TOM-Complex-Mediated Import by Ubx2. Trends Cell Biol. 2019;29(9):687-689 [Lire l’article]


Fava VM, Xu YZ, Lettre G, Van Thuc N, Orlova M, Thai VH, Tao S, Croteau N, Eldeeb MA, MacDougall EJ, Cambri G, Lahiri R, Adams L, Fon EA, Trempe JF, Cobat A, Alcaïs A, Abel L, Schurr E. Pleiotropic effects for Parkin and LRRK2 in leprosy type-1 reactions and Parkinson's disease. Proc Natl Acad Sci U S A. 2019;116(31):15616-15624 [Lire l’article]


Eldeeb MA, Ragheb MA, Fon EA. Cell Death: N-degrons Fine-Tune Pyroptotic Cell Demise. Curr Biol. 2019;29(12):R588-R591 [Lire l’article]


Eldeeb MA, Fahlman RP, Esmaili M, Fon EA. When Degradation Elicits the Alarm: N-Terminal Degradation of NLRP1B Unleashes Its Inflammasome Activity. Mol Cell. 2019;74(4):637-639 [Lire l’article]


Yi W, MacDougall EJ, Tang MY, Krahn AI, Gan-Or Z, Trempe JF, Fon EA. The landscape of Parkin variants reveals pathogenic mechanisms and therapeutic targets in Parkinson's disease. Hum Mol Genet. 2019;28(17):2811-2825 [Lire l’article]


Alcalay RN, Mallett V, Vanderperre B, Tavassoly O, Dauvilliers Y, Wu RYJ, Ruskey JA, Leblond CS, Ambalavanan A, Laurent SB, Spiegelman D, Dionne-Laporte A, Liong C, Levy OA, Fahn S, Waters C, Kuo SH, Chung WK, Ford B, Marder KS, Kang UJ, Hassin-Baer S, Greenbaum L, Trempe JF, Wolf P, Oliva P, Zhang XK, Clark LN, Langlois M, Dion PA, Fon EA, Dupre N, Rouleau GA, Gan-Or Z. SMPD1 mutations, activity, and α-synuclein accumulation in Parkinson's disease. Mov Disord. 2019;34(4):526-535 [Lire l’article]


Mohamed NV, Mathur M, Da Silva RV, Beitel LK, Fon EA, Durcan TM. Generation of human midbrain organoids from induced pluripotent stem cells. MNI Open Research 2019 [Lire l’article]


Mohamed NV, Larroquette F, Beitel LK, Fon EA, Durcan TM. One Step Into the Future: New iPSC Tools to Advance Research in Parkinson's Disease and Neurological Disorders. J Parkinsons Dis. 2019;9(2):265-281 [Lire l’article]


Eldeeb MA*, Fahlman RP, Esmalili M, Fon EA. Formylation of Eukaryotic Cytoplasmic Proteins:Linking Stress to Degradation. Trends Biochem, Sci. 2019; 181-183 [Lire l’article]


Rudakou U, Ouled Amar Bencheikh B, Ruskey JA, Krohn L, Laurent SB, Spiegelman D, Liong C, Fahn S, Waters C, Monchi O, Fon EA, Dauvilliers Y, Alcalay RN, Dupré N, Gan-Or Z. Common and rare GCH1 variants are associated with Parkinson's disease. Neurobiol. Aging. 2019; 73:231.e1-231.e6. [Lire l’article]


McLelland GL*, Fon EA. MFN2 retrotranslocation boosts mitophagy by uncoupling mitochondria from the ER. Autophagy. 2018; 1658-1660. [Lire l’article]


McLelland GL*, Fon EA. Principles of mitochondrial vesicle transport. Curr. Opin. Physiol. 2018; 3:25–33. [Lire l’article]


Ouled Amar Bencheikh B, Leveille E, Ruskey JA, Spiegelman D, Liong C, Fon EA, Rouleau GA, Dauvilliers Y, Dupre N, Alcalay RN, Gan-Or Z. Sequencing of the GBA coactivator, Saposin C, in Parkinson disease. Neurobiol. Aging. 2018; S0197-4580(18)30239-2.–33. [Lire l’article]


Ruskey JA, Zhou S, Santiago R, Franche LA, Alam A, Roncière L, Spiegelman D, Fon EA, Trempe JF, Kalia LV, Postuma RB, Dupre N, Rivard GE, Assouline S, Amato D, Gan-Or Z. The GBA p.Trp378Gly mutation is a probable French-Canadian founder mutation causing Gaucher disease and synucleinopathies.  Clin. Genet. 2018; [Lire l’article]


Bell S, Maussion G, Jefri M, Peng H, Theroux JF, Silveira H, Soubannier V, Wu H, Hu P, Galat E, Torres-Platas SG, Boudreau-Pinsonneault C, O'Leary LA, Galat V, Turecki G, Durcan TM, Fon EA, Mechawar N, Ernst C. Disruption of GRIN2B Impairs Differentiation in Human Neurons. Stem Cell Reports. 2018; S2213-6711(18)30236-4 [Lire l’article]


Li J, Ruskey JA, Arnulf I, Dauvilliers Y, Hu MTM, Högl B, Leblond CS, Zhou S, Ambalavanan A, Ross JP, Bourassa CV, Spiegelman D, Laurent SB, Stefani A, Charley Monaca C, Cochen De Cock V, Boivin M, Ferini-Strambi L, Plazzi G, Antelmi E, Young P, Heidbreder A, Labbe C, Ferman TJ, Dion PA, Fan D, Desautels A, Gagnon JF, Dupré N, Fon EA, Montplaisir JY, Boeve BF, Postuma RB, Rouleau GA, Ross OA and Gan-Or Z. Full sequencing and haplotype analysis of MAPT in Parkinson disease and REM sleep behavior disorder. Mov. Disord. 2018; [Lire l’article]


McLelland GL*, Goiran T*, Yi W*, Dorval G, Chen CX, Lauinger ND*, Krahn AI*, Valimehr S, Rakovic A, Rouiller I, Durcan TM, Trempe JF, Fon EA. Mfn2 ubiquitination by PINK1/parkin gates the p97-dependent release of ER from mitochondria to drive mitophagy. Elife. 2018; 7.pii: e32866. [Lire l’article]


Mohtashami S, He Q, Ruskey JA, Zhou S, Dion PA, Allen RP, Earley CJ, Fon EA, Xiong L, Dupre N, Dauvilliers Y, Rouleau GA, Gan-Or Z. TOX3 Variants Are Involved in Restless Legs Syndrome and Parkinson's Disease with Opposite Effects. J. Mol. Neurosci. 2018; 64(3):341-345. [Lire l’article]


Ross JP, Mohtashami S, Leveille E, Johnson AM, Xiong L, Dion PA, Fon EA, Dauvilliers Y, Dupré N, Rouleau GA, Gan-Or Z. Association study of essential tremor genetic loci in Parkinson's disease. Neurobiol. Aging. 2018; 66:178.e13-178.e15. [Lire l’article]


Manecka DL*, Vanderperre B*, Fon EA, Durcan TM. The Neuroprotective Role of Protein Quality Control in Halting the Development of Alpha-Synuclein Pathology. Front. Mol. Neurosci. 2017; 10: 311. [Lire l’article]


Tang MY*, Vranas M, Krahn A*, Pundlik S*, Trempe JF, Fon EA. Structure-guided mutagenesis reveals a hierarchical mechanism of Parkin activation. Nat. Commun. 2017; 8: 14697. [Lire l’article]


Rodriguez L, Mohamed NV, Desjardins A, Lippé R, Fon EA, Leclerc N. Rab7A regulates Tau secretion. J. Neurochem. 2017; 141(4):592-605. [Lire l’article]


Roberts RF*, Fon EA. Presenting mitochondrial antigens: PINK1, Parkin and MDVs steal the show. Cell Res. 2016; 26(11):1180-1181. [Lire l’article]


Roberts RF*, Tang MY*, Fon EA, Durcan TM. Defending the mitochondria: The pathways of mitophagy and mitochondrial-derived vesicles. Int. J. Biochem. Cell. Biol. 2016; 79:427-436. [Lire l’article]


Munoz DP, Fon EA, Chen R. A New Collaboration Between the Canadian Association for Neuroscience and CJNS. Can. J. Neurol. Sci. 2016; 43(1):2. [Lire l’article]


McLelland GL*, Lee SA*, McBride HM, Fon EA. Syntaxin-17 delivers PINK1/parkin-dependent mitochondrial vesicles to the endolysosomal system. J. Cell Biol. 2016; 214(3):275-91. [Lire l’article]


Schreij AM, Fon EA, McPherson PS. Endocytic membrane trafficking and neurodegenerative disease. Cell. Mol. Life Sci. 2016; 73(8):1529-45. [Lire l’article]


Durcan TM*, Fon EA. The three P’s of Mitophagy: PARKIN, PINK1 and Post-Translational Modifications. Genes Dev. 2015; 29(10):989-999. [Lire l’article]


Ryan BJ, Hoek S, Fon EA, Wade-Martins R. Mitochondrial dysfunction and mitophagy in Parkinson's: from familial to sporadic disease. Trends Biochem. Sci. 2015; 40(4):200-210. [Lire l’article]


Durcan TM*, Fon EA. USP8 and PARK2/parkin-mediated mitophagy. Autophagy. 2015; 11(2):428-9. [Lire l’article]


Aguileta MA*, Korac J, Durcan TM*, Trempe JF*, Haber M*, Gehring K, Elsasser S, Waidmann O, Fon EA, Husnjak K. The E3 Ubiquitin ligase parkin is recruited to the 26S proteasome via the proteasomal ubiquitin receptor Rpn13. J Biol Chem. 2015; 290(12):7492-505. [Lire l’article]


Bertolin G, Jacoupy M, Traver S, Ferrando-Miguel R, Saint Georges T, Grenier K*, Ardila-Osorio H, Muriel MP, Takahashi H, Lees AJ, Gautier C, Guedin D, Coge F, Fon EA, Brice A, Corti O. Parkin maintains mitochondrial levels of the protective Parkinson's disease-related enzyme 17-β hydroxysteroid dehydrogenase type 10. Cell Death Differ. 2015; 22(10):1563-76. [Lire l’article]


Schreij AMA*, Chaineau M, Ruan W, Lin S, Barker, PA, Fon EA§, McPherson PS§. LRRK2 localizes to endosomes and interacts with clathrin-light chains to limit Rac1 activation. EMBO Rep. 2015; 16(1):79-86. §co-corresponding authors [Lire l’article]


Grenier K*, Kontogiannea M*, Fon EA. Short mitochondrial ARF triggers Parkin/PINK1-dependent mitophagy in neurons. J. Biol. Chem. 2014; 289(43):29519-30 [Lire l’article]


Durcan TM*, Tang MY*, Pérusse JR, Dashti EA*, Aguileta MA*, McLelland GL*, Gros P*, Shaler TA, Faubert D, Coulombe B, Fon EA. USP8 Regulates Mitophagy by Removing K6-linked Ubiquitin Conjugates from Parkin. EMBO J. 2014; 33(21):2473-91 [Lire l’article]


Sugiura A, McLelland GL*, Fon EA, McBride HM. A new Pathway for Mitochondrial Quality Control: Mitochondrial Derived Vesicles. EMBO J. 2014; 33(19):2142-2156 [Lire l’article]


Koyano F, Okatsu K, Kosako H, Tamura Y, Go E, Kimura M, Kimura Y, Tsuchiya H, Yoshihara H, Hirokawa T, Endo T, Fon EA, Trempe JF, Saeki Y, Tanaka K, Matsuda N. Ubiquitin is phosphorylated by PINK1 to activate parkin. Nature. 2014; 510(7503):162-6 [Lire l’article]


McLelland GL*, Soubannier V, Chen CX*, McBride HM, Fon EA. Parkin and PINK1 Function in a Vesicular Trafficking Pathway Regulating Mitochondrial Quality Control. EMBO J. 2014; 33(4):282-95. [Lire l’article]


Bertolin G, Ferrando-Miguel R, Jacoupy M, Traver S, Grenier K*, Greene AW*, Dauphin A, Waharte F, Bayot A, Salamero J, Lombès A, Bulteau AL, Fon EA, Brice A, Corti O. The TOMM machinery is a molecular switch in PINK1 and PARK2/PARKIN-dependent mitochondrial clearance. Autophagy. 2013; 9(11):1801-17 [Lire l’article]


Grenier K*, McLelland GL*, Fon EA. Parkin- and PINK1-Dependent Mitophagy in Neurons: Will the Real Pathway Please Stand Up? Front Neurol. 2013; 4:100 [Lire l’article]


Trempe J-F*, Sauvé, V*, Grenier K, Seirafi, M, Tang MY, Ménade M, Krett J, Wong K, Kozlov G, Nagar B, Fon EA§, Gehring K§. Structure of parkin reveals mechanism of ubiquitin ligase activation. Science. 2013; 340: 1451-55 Epub 2013 May 9. §co-corresponding authors. [Lire l’article]


Durcan TM*, Fon EA. Ataxin-3 and its E3 partners: Implications for Machado-Joseph disease.  Front. Neur. 2013 4:46. [Lire l’article]


Trempe JF*, Fon EA. Structure and function of parkin, PINK1 and DJ-1, the three musketeers of neuroprotection.Front. Neur. 2013. 4:38. [Lire l’article]


Ruan W*, Unsain N, Desbarats J, Fon EA§, Barker PA§. Wengen, the Sole Tumour Necrosis Factor Receptor in Drosophila, Collaborates with Moesin to Control Photoreceptor Axon Targeting During Development. PLoS One2013; 8(3): e60091. §co-corresponding author [Lire l’article]


Daoud H, Noreau A, Rochefort D, Paquin-Lanthier G, Gauthier MT, Provencher P, Pourcher E, Dupré N, Chouinard S, Jodoin N, Soland V, Fon EA, Dion PA, Rouleau GA. Investigation of C9orf72 repeat expansions in Parkinson's disease. Neurobiol Aging. 2013 Jun; 34(6): 1710.e7-9. doi: 10.1016/j.neurobiolaging.2012.11.025 [Lire l’article]


Grimes D, Gordon J, Snelgrove B, Lim-Carter I, Fon E, Martin W, Wieler M, Suchowersky O, Rajput A, Lafontaine AL, Stoessl J, Moro E, Schoffer K, Miyasaki J, Hobson D, Mahmoudi M, Fox S, Postuma R, Kumar H, Jog M; Canadian Neurological Sciences Federation. Canadian Guidelines on Parkinson's Disease. Can J Neurol Sci. 2012 Jul;39 (4 Suppl 4):S1-30 [Lire l’article]


Klionsky DJ et al. Guidelines for the use and interpretation of assays for monitoring autophagy. Autophagy. 2012 Apr;8(4):445-544 [Lire l’article]


Greene AW*, Grenier K*, Aguileta MA, Muise S, Farazi R, Haque ME, McBride HM, Park DS, Fon EA. Mitochondrial Processing Peptidase Regulates PINK1 Processing, Import and Parkin Recruitment. EMBO Rep. 2012; 13(4):378-85 [Lire l’article]


Soubannier V, McLelland GL, Zunino R, Braschi E, Rippstein P, Fon EA, McBride HM. A novel vesicular transport pathway shuttles cargo from mitochondria to lysosomes. Curr. Biol. 2012; 22(2):135 [Lire l’article]


Durcan TM, Kontogiannea M, Bedard N, Wing SS, Fon EA. Ataxin-3 deubiquitination is coupled to parkin ubiquitination via the E2 ubiquitin-conjugating enzyme. J. Biol. Chem. 2012; 287(1):531-41 [Lire l’article]


Durcan TM, Fon EA. Mutant ataxin-3 promotes the autophagic degradation of parkin. Autophagy. 2011; 7(2):233-4 [Lire l’article]


Durcan TM*, Kontogiannea M*, Thorarinsdottir T, Fallon L, Williams AJ, Djarmati A, Fantaneanu T, Paulson HL, Fon EA. The Machado-Joseph Disease-Associated Mutant form of Ataxin-3 Regulates Parkin Ubiquitination and Stability. Hum. Mol. Genet. 2011; 20(1):141-54 [Lire l’article]


Irrcher I, Aleyasin H, Seifert EL, Hewitt SJ, Chhabra S, Phillips M, Lutz AK, Rousseaux MW, Bevilacqua L, Jahani-Asl A, Callaghan S, Maclaurin JG, Winklhofer KF, Rizzu P, Rippstein P, Kim RH, Chen CX, Fon EA, Slack RS, Harper ME, McBride HM, Mak TW, Park DS. Loss of the Parkinson's Disease-linked gene DJ-1 perturbs mitochondrial dynamics. Hum. Mol. Genet. 2010; 19(19):3734-46 [Lire l’article]


Théard D, Labarrade F, Partisani M, Milanini J, Sakagami H, Fon EA, Wood SA, Franco M, Luton F. USP9x-mediated deubiquitination of EFA6 regulates de novo tight junction assembly. EMBO J. 2010;29(9):1499-509 [Lire l’article]


Bouvier D, Tremblay ME, Riad M, Corera AT, Gingras D, Horn KE, Fotouhi M, Girard M, Murai KK, Kennedy TE, McPherson PS, Pasquale EB, Fon EA, Doucet G. EphA4 is localized in clathrin-coated and synaptic vesicles in adult mouse brain. J. Neurochem. 2010; 113:153-165 [Lire l’article]


Trempe JF*, Chen CXQ*, Grenier K, Camacho EM, Kozlov G, McPherson PS, Gehring K, Fon EA. SH3 Domains from a Subset of BAR-Proteins Define a Novel Ubl-Binding Domain and Implicate Parkin in Synaptic Ubiquitination. Mol. Cell 2009; 36(6):1034-47. Co-corresponding authors [Lire l’article]


Corera AT, Doucet G, Fon EA. Long-Term Potentiation in Isolated Dendritic Spines. PLoS ONE. 2009; 4(6): e6021. doi:10.1371/journal.pone.0006021. [Lire l’article]


Cookson MR, Dauer W, Dawson TM, Fon EA, Guo M, Shen J. The roles of kinases in familial Parkinson’s disease. J. Neurosci. 2007; 27(44):11865-8 [Lire l’article]


Kaiser P, Fon EA. Keystone Meeting on Ubiquitin and Signaling: Expanding Horizons at Big Sky. EMBO Rep. 2007; 8(9):817-22. [Lire l’article]


Joch M*, Ase AR*, Chen CXQ*, MacDonald PA, Kontogiannea M, Corera AT, Brice A, Séguéla P, Fon EA. Parkin-Mediated Monoubiquitination of the PDZ Protein PICK1 Regulates ASIC Channel Activity. Mol. Biol. Cell. 2007; 18(8):3105-18[Lire l’article]


Zhou L, Martinez SJ, Haber M, Jones EV, Bouvier D, Doucet G, Corera AT, Fon EA, Zisch AH, Murai KK. EphA4 signaling regulates phospholipase Cgamma1 activation, cofilin membrane association, and dendritic spine morphology. J. Neurosci. 2007; 27(19):5127-38. [Lire l’article]


Fallon L, Bélanger CML, Corera AT, Kontogiannea M, Regan-Klapisz E, Moreau F, Voortman J, Haber M, Rouleau G, Thorarinsdottir T, Brice A, van Bergen en Henegouwen P, Fon EA. A Regulated Interaction with the UIM-protein Eps15 Implicates Parkin in EGF Receptor Trafficking and PI3K-Akt Signaling.Nat. Cell Biol. 2006; 8(8):834-42 [Lire l’article]


Kalia SK, Lee S, Liu L, Crocker SJ, Thorarinsdottir TE, Smith PD, Glover JR, Fon EA, Park DS, Lozano AM. BAG5 inhibits parkin and enhances dopaminergic neuron degeneration. Neuron 2004; 44(6):931-45. [Lire l’article]

 

Notre laboratoire fait partie du Neuro (Institut et Hôpital neurologiques de Montréal), à l'institut de recherche et d'enseignement McGill, qui offre des soins de haut calibre aux patients, dans le cadre de la Mission en neurosciences du Centre universitaire de santé McGill.

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