Lysosomal Biology and Autophagy

PROFILE

Discoveries from recent years have elevated the lysosome from their classical role as a degradative intracellular compartment to a signal integrator and critical regulator of cellular growth, functionality, and survival. In addition to their role in lysosomal storage diseases, several developmental and chronic diseases have been associated with lysosome-related dysfunctions; however, many of the involved mechanisms are unknown. Our main objective is to elucidate the molecular mechanisms that explain how lysosomes integrate and execute stimulus from other parts of the cells and how the lysosomes communicate with other organelles to contribute to cell homeostasis during normal and pathological conditions. The main areas of research in our lab involve the characterization of the role and regulation of autophagy-lysosomal systems during neuronal synaptic development and synaptic maintenance in aging and neurodegenerative diseases; the molecular and pharmacological characterization of selective lipophagy activation in liver cells; the communication between lysosome with stress signaling pathways; and the physiology of the lysosomal membrane and its interaction with pharmacological drugs.

LAB MEMBERS

Research Head: Iván Alfaro

Doctoral students: Felipe Pérez de Arce • Juan Hormazábal

Undergraduate students: Rodrigo Espinosa • Tamara Rojas

Research assistants: Javiera de la Cruz Serrat • Andrea Riveros • Claudia Espinoza 

COLLABORATIONS

National Collaborations:

  • Rebeca Aldunate (Universidad Santo Tomás). Autophagy processes in C. elegans models of proteinopathies and aging.
  • Sebastián Bernales (Fundación Ciencia & Vida). Pharmacological modulation of autophagy pathways and autophagy crosstalk with stress signaling pathways.
  • Alejandra Loyola (Fundación Ciencia & Vida). Cytosolic histone degradation by chaperone mediated autophagy.
  • Alejandro Madrid (Universidad de Playa Ancha). Studies of plant extracts and natural derived stilbenes as autophagy modulators in cancer and neuronal cells.

International Collaborations:

  • Ana María Cuervo (Albert Einstein College of Medicine). Chaperone-mediated autophagy mechanisms and regulation in health and disease.
  • Rajat Singh (Albert Einstein College of Medicine). Pharmacological modulation of lipophagy in non-alcoholic steatohepatitis.

SELECTED PUBLICATIONS

  • Ramachandran SA, Jadhavar PS, Miglani SK, Singh MP, Kalane DP, Agarwal AK, Sathe BD, Mukherjee K, Gupta A, Haldar S, Raja M, Singh S, Pham SM, Chakravarty S, Quinn K, Belmar S, Alfaro IE, Higgs C, Bernales S, Herrera FJ, Rai R. (2017) Design, synthesis and optimization of bis-amide derivatives as CSF1R inhibitors. Bioorg Med Chem Lett. Mar 24. pii: S0960-894X(17)30314-1. doi: 10.1016/j.bmcl.2017.03.064 | | ABSTRACT
  • Jadhavara PS, Ramachandrana SA, Riquelme E, Guptaa A, Quinnc KP, Shivakumard D, Rayd S, Zendea D, Nayaka AK, Miglania SK, Sathea BD, Rajaa M, Farias O, Alfaro IE, Belmar S, Guerrero J, Bernales S, Chakravartyc S, Hung DT, Lindquist JN, Raic R (2016). Targeting prostate cancer with compounds possessing dual activity as androgen receptor antagonists and HDAC6 inhibitors. Bioorg Med Chem Lett. 26(21):5222-5228. | | ABSTRACT
  • Parodi J, Montecinos-Oliva C, Varas R, Alfaro IE, Serrano FG, Varas-Godoy M, Muñoz FJ, Cerpa W, Godoy JA, Inestrosa NC (2015) Wnt5a inhibits K(+) currents in hippocampal synapses through nitric oxide production. Mol Cell Neurosci. 68:314-22. | | ABSTRACT
  • Alfaro IE, Varela-Nallar L, Varas-Godoy M, Inestrosa NC. (2015) The ROR2 tyrosine kinase receptor regulates dendritic spine morphogenesis in hippocampal neurons. Mol Cell Neurosci. 67:22-30. | | ABSTRACT
  • Cochrane DR, Bernales S, Jacobsen BM, Cittelly DM, Howe EN, D'Amato NC, Spoelstra NS, Edgerton SM, Jean A, Guerrero J, Gómez F, Medicherla S, Alfaro IE, McCullagh E, Jedlicka P, Torkko KC, Thor AD, Elias AD, Protter AA, Richer JK (2014) Role of the androgen receptor in breast cancer and preclinical analysis of enzalutamide. Breast Cancer Res. 16(1):R7. | | ABSTRACT
  • Guerrero J, Alfaro IE, Gómez F, Protter AA, Bernales S (2013) Enzalutamide, an Androgen Receptor Signaling Inhibitor, Induces Tumor Regression in Mouse Model of Castration-Resistant Prostate Cancer. Prostate. 73(12):1291-305. | | ABSTRACT
  • Quintanilla RA, Godoy JA, Alfaro IE, Cabezas D, Von Bernhardi R, Bronfman M, Inestrosa NC (2013) Thiazolidinediones Promote Axonal Growth through the Activation of the JNK Pathway. PLoS One. 8(5):e65140. doi: 10.1371/journal.pone.0065140. | | ABSTRACT
  • Steele JW, Lachenmayer ML, Ju S, Stock A, Liken J, Kim SH, Delgado LM, Alfaro IE, Bernales S, Verdile G, Bharadwaj P, Gupta V, Barr R, Friss A, Dolios G, Wang R, Ringe D, Fraser P, Westaway D, St George-Hyslop PH, Szabo P, Relkin NR, Buxbaum JD, Glabe CG, Protter AA, Martins RN, Ehrlich ME, Petsko GA, Yue Z, Gandy S. (2012) Latrepirdine improves cognition and arrests progression of neuropathology in an Alzheimer's mouse model. Mol. Psychiatry. 31 Jul 2012, doi: 10.1038/mp.2012.106. | | ABSTRACT
  • Steele JW, Ju S, Lachenmayer ML, Liken J, Stock A, Kim SH, Delgado LM, Alfaro IE, Bernales S, Verdile G, Bharadwaj P, Gupta V, Barr R, Friss A, Dolios G, Wang R, Ringe D, Protter AA, Martins RN, Ehrlich ME, Yue Z, Petsko GA, Gandy S. (2012) Latrepirdine stimulates autophagy and reduces accumulation of α-synuclein in cells and in mouse brain. Mol Psychiatry. 7 August 2012, doi: 10.1038/mp.2012.115. | | ABSTRACT
  • Giorgetti M, Gibbons JA, Bernales S, Alfaro IE, Drieu La Rochelle C, Cremers T, Altar CA, Wronski R, Hutter-Paier B, Protter AA. (2010) Cognition-enhancing properties of Dimebon in a rat novel object recognition task are unlikely to be associated with acetylcholinesterase inhibition or N-methyl-D-aspartate receptor antagonism. J Pharmacol Exp Ther. 333(3):748-57. | | ABSTRACT
  • Varela-Nallar L, Alfaro IE, Serrano FG, Parodi J, Inestrosa NC. (2010) Wingless-type family member 5A (Wnt-5a) stimulates synaptic differentiation and function of glutamatergic synapses. Proc Natl Acad Sci USA. 107(49):21164-9. | | ABSTRACT

PATENTS

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