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Lisosoma Autofagia Mediada Por Chaperonas Autofagia en la defense contra el envejecimiento Ana Maria Cuervo MD PhD Department of Developmental and Molecular Biology Marion Bessin Liver Research Center Institute for Aging Research Albert Einstein College of Medicine Bronx, New York, USA Agradecimientos Mis padres…. por tantas y tantas cosas… Agradecimientos Erwin Knecht Departamento de fisiologia Ximo Roma Fred Dice Agradecimientos Fernando Macian Los verdaderos protagonistas…. Susmita Eloy Esperanza Bindi Benjamin Inmaculada Antonio Qixheng Luisa Julio Nadia Luciana Shuxian Yves Phillip Erika Kumsal Ashish Urmi Judy Guy Marta Roberta Esther Alejandro Masha Hiroshi Lori Jose Jaime Sunandini Samantha Jaime Caroline Joan Olatz Barbara Autofagia en la defense contra el envejecimiento Ana Maria Cuervo MD PhD Department of Developmental and Molecular Biology Marion Bessin Liver Research Center Institute for Aging Research Albert Einstein College of Medicine Bronx, New York, USA CONTROL DE CALIDAD CELULAR Jovenes Viejos/Patologias ATP . O Radicales InsultO. Libres O. Proteina Proteina Chaperonas Reparada Proteasas Chaperonas Amino acidos Agregados Proteasas Las celulas tienen muchos sistemas de limpieza Enfermo/Viejo Sano/Joven Proteina Normal Proteina dañada Autofagia Proteinas Organellas Patogenos lisosomas Autofagia Tipos de Autofagia in Mamíferos Autofagia Mediada por Chaperonas Microautofagia Macroautofagia Lisosoma Kaushik and Cuervo (Trends Cell Biol) 2012 Cuervo and Macian (Mol Aspects Med) 2011 Funciones de la autofagia Energia Remodelado Enfermedades Osteoporosis metabolicas Diabetes, obesidad ENVEJECIMIENTO Reprogramar Cancer Control de Calidad Defense Proteinas dañadas Immunosenescencia Enfermedades Neurodegenerativas Organelas dañadas AD, PD, HD Renovacion de organelas Autofagia y el Envejecimiento 1 Porque no funciona? 2 Cuales son las consecuencias? 3 Podemos repararla? Lysosome Autofagia mediada por chaperonas (CMA) Proteina substrato Chaperona (hsc70/cochaperones) KFERQ LAMP-2A Complejo de translocacion Lys hsc70 Lisosoma Kaushik and Cuervo, Nature Medicine (2015) Kaushik and Cuervo, Trends in Cell Biology (2012) Arias and Cuervo, Current Opinion in Cell Biology (2010) Autofagia mediada por chaperonas (CMA) Proteina substrato Chaperona (hsc70/cochaperones) Rac-1 LAMP-2A PHLLP KFERQ ? Complejo de translocacion Lys hsc70 AKT Lisosoma TORC2 Kaushik and Cuervo, Nature Medicine (2015) Kaushik and Cuervo, Trends in Cell Biology (2012) Arias and Cuervo, Current Opinion in Cell Biology (2010) Fallo functional de la autofagia en viejos Edad (meses) 3 m 22 m 3 m 22 m 2A - LAMP Edad (años) 25y 65y 25y 65y 2A - LAMP Los niveles lisosomales de LAMP-2A disminuyen con la edad Lisosoma D. Sulzer R. Nixon CMA y neurodegeneracion H. Ischiropolus L. Thompson A. Consiglio/ A. Raya Proteina LRRK2 patogenica VPS35 SYN vkkdq Substratos Enfermedad de Parkinson CMA TAU qvevk kdrvq Enfermedad de Alzheimer/Taup. qervl qkevv qvkld HTT Enfermedad de Huntington Orenstein el al. (2013)Nat Neurosci Koga el al. (2011) J. Neurosci Wang et al. (2009) Hum. Mol. Genetics Martinez-Vicente et al. (2008) J. Clin. Invest. Mak et al. (2010) J. Biol. Chem. Cuervo et al. (2004) Science D. Sulzer R. Nixon CMA y neurodegeneracion HCONDICIONES. Ischiropolus NORMALES L. Thompson Proteina LRRK2 patogenica VPS35 SYN vkkdq Substratos Enfermedad de Parkison CMA LRRK2 TAU Orenstein el al. (2013)Nat Neurosci TAU qvevk kdrvq Cytosol MT Cytosol LRRK2 Ac-Tau LRRK2 Enfermedad de Alzheimer/tauop. Control AD qervl qkevv qvkld 700 700 kDa HTT Multimer 2A - Enfermedad de Huntington LAMP-2A LAMP LAMP-2A Orenstein el al. (2013)Nat Neurosci Lysosomal lumen Lysosomal lumen Koga el al. (2011) J. Neurosci Wang et al. (2009) Hum.mt Mol. Genetics mt Tau inhibe el 110 110 kDa LRRK2 bloquea la Martinez-Vicente et al. (2008) J. Clin. Invest. Monomer desensamblado de multimerizacion de L2A Mak et al. (2010) J. Biol. Chem. Cuervo et al. (2004) ScienceL2A Autofagia y el Envejecimiento 1 Porque no funciona? 2 Cuales son las consecuencias? 3 Podemos repararla? Lysosome Fisiologia de la autofagia mediada por chaperonas PROTEO -TOXICIDAD GENO-TOXICIDAD MNR + + Kiffin et al. Mol Biol Cell (2004) Cuervo at al. Science (2004) Zhang and Cuervo, Nat Med (2008) CMA Park et al Nat Commun (2015) Martinez-Vicente et al, JCI (2010) Orenstein et al Nat Neurosci (2013) ESTRES NUTRICIONAL LIPO-TOXICIDAD + Gotas lipidicas Lysosome Ayuno prolongado + Metabolismo de la glucose en Cancer Cuervo et al. Am. J. Physiol (1995) Kaushik et al. EMBO J (2008) Cuervo et al. J Biol Chem (1997) Rodriguez Navarro et al. PNAS (2012) Kon et al. Science Translation (2011) En vivo? Bloqueo en vivo de CMA LAMP2A KO Jaime Schneider LAMP-2 gene I II III VIII VIII VIII X Chromosome B A C Julio Madrigal Bienvenidos a nuestroLuisa Jaime Schneider Coletto Esperanza Inma Kumsal J A Rodriguez f/f f/f L2A L2A L2Af/f Alb + cre MICE + + TH cre + Camk2a-cre HSA cre Alb-L2A MICE LAMP2A -/- MICE THL2A MICE CKL2A MICE HSAL2A MICE Corteza Musculo Cuerpo Hepatocitos Talamo (Hipocampus, completo Cerebelo SN) Patologia de CMA: Neurodegeneracion WT Total tau Tau Anormal Perdida de CMA en el cerebro resulta en perdida de proteostasis y neurodegeneracion Jaime Schneider CMA regula el metabolismo SusmitaAlb-Cre- Proteinas de union y Kaushik LAMP-2Af/f transporte de lipidos APOC1 APOOL Glucosa ATP11c Tpi1 Glycerol-3-P FBP1 ALDO A ALDO B GAPDH GPD2 Dgat2 PKM ENOLASE LDH1 ACBP Glicolisis ALDH1a1 BHMT ? Piruvato Acetyl-CoA Sintesis de trigliceridos Cs Mdh1 Idh1 TCA Cycle Metabolismo Metabolismo Fh Idh3a de lipidos de carbohidratos Perilipinas – nuevos substrates de CMA Susmita Kaushik PLN2 PLN3 Cyt-Hsc70 PLN2 PLN3 Lipasa citosolica FA LAMP-2A LAMP-2A beta-oxidation FA Cyt-Hsc70 Lys-Hsc70 Lisosoma (lipasa acidica) Lysosome Kaushik and Cuervo, Nat. Cell. Biol. (2015) Perilipinas – nuevos substrates de CMA Susmita Lysosos Kaushik PLN2 PLN3 PLN2 PLN3 hsc70 PLN2 LAMP-2A lLipasa citosolica FA LAMP-2A LAMP-2A PLN3 beta-oxidation FA Cyt-Hsc70 Hsc70 Lisosoma (lipase acida) Lysosome Kaushik and Cuervo, Nat. Cell. Biol. (2015) Julio CMA en el metabolismo Madrigal Anormalias Anomalias Enfermedad metabolicas metabolicas sistemica WT Alb- L2A-/- locales sistemmicas WT L2A KO S PA Diabetes Sindrome Obesidad Higado Red metabolico Obesidad - o - Oil Tejido adiposo Enfermedades Disregulacion enzimatica Fallo para cardiovasculares eliminar las -/- Hepato- perilipinas Musculo LAMP2A MICE esqueletico steatosis Enfermedad Pancreas hepatica Resistencia a la insulina Cuerpo entero SNC Autofagia y el Envejecimiento CC 1 Porque no funciona? Estres Metabolismo 2 Cuales son las consecuencias? 3 Podemos repararla? Lisosoma Autofagia en Centenarios Dr. Fernando Ignacio Macian Guerrero G. Atzmon N. Barzilai Yves Juste Niveles de LAMP-2A Descendientes 1600 No descendients de centenarios 1400 de centenarios 1200 T cell 1000 800 600 400 Mejor defensa immune 2A (arbitrary densitometric units) densitometric (arbitrary 2A 200 - 0 Lamp 6922 6868 6851 6835 2587 7743 7724 7685 7652 7633 Mejor respuesta de las células T Centenarios tienen mejor autofagia! Manteniendo CMA actia!! Antonio Diaz E. Gavathiotis Qisheng Xin ¿Diana RARa terapeutica? Anguiano et al. Nat. Chem. Biol. (2013) Autophagy y el envejecimiento Remodelado del Proteoma Envejecimiento Diabetes Obesidad Dieta Control de Calidad Proteotoxicidad Energetica Neurons Metabolismo Liver Lipolisis PHLLP Glycolisis Activacion Programada Valdor et al. Nature Immunology (2014) AKT F. Macian Diferenciacion T cell TORC2 Diana Ciclo celular terapeutica Reparacion DNA Collaborators Acknowledgements David Sulzer (Columbia University) Sheng Zhang (UTSW, TX) The Ralph Nixon (New York U) E+E Mandelkow (Max Plank, GRM) Cuervo D. DiMonte (U. Bonn) Patricia Boya (CMB) Lab Gil De Paolo (Columbia University) Patrice Codogno (INSERM, Fr) A. Consiglio / A. Raya (IBUB/CMRB) Li Gan (Gladstone, SF) Ander Matute (Biogune) Francesc Villaroya (U. Barcelona) Evris Gavathiotis David Spray Andreas Jenny Yousin Suh Current Members Alumni Richard Kitsis L. Santambrogio Fernando Macian Vlad Verkhusha Esperanza Arias Yves R Juste Jaime Anguiano Sunandini Sridhar B and P Satir Allan Wolkoff Samanta Orenstein Eloy Bejarano Urmi Bandyopadhyay Rajat Singh Susmita Kaushik Roberta Kiffin Caroline Park Benja Caballero Philipp Kirchner Maria Kon Jose Rodriguez Luisa Coletto Julio Madrigal Marta Martinez-Vicente Jaime Schneider Ashish Massey Barbara Stiller Antonio Diaz Bindi Patel Joan Villarroya Olatz Pampliega Current Funding Shuxian Dong Nadia Storm Alejandro Quiroga Esther Wong Erika Garay Inma Tasset Guy Sovak Cong Zhang Luciana Gomes Lori Spoozak NIH/NIA MJ Fox Foundation Qisheng Xin NIH/NIDDK Beatrice Bacus Foundation NIH/NINDS Rainwaters Foundation.
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