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Carlos R. Morales, Ph.D.
Department of Anatomy and Cell Biology
McGill University
3640 rue University
Montréal, Qc, H3A 0C7
This email address is being protected from spambots. You need JavaScript enabled to view it.
fax 514-398-5047
Lab.: 514-398-8921

 

Research Interests

  • Biogenesis of Lysosomes
  • Lysosomal Sphingolipid Activator Proteins (SAPs)
  • Targeting Mechanisms of lysosomal Proteins
  • Studies on Reproduction

Studies on Lysosomes

Sphingolipid activator proteins (SAPs) are five non-enzymatic cofactors required for the lysosomal degradation of glycosphingolipids. Four of them are the saposins A, B, C and D, which derive from the precursor protein, prosaposin. Prosaposin mutations are responsible for the variant forms of the lysosomal storage disorders, Gaucher’s disease and metachromatic leukodystrophy. The fifth activator, the GM2 Activator Protein (GM2AP), is the product of a distinct gene and is an essential cofactor for hexosaminidase A in the degradation of GM2 to GM3 ganglioside. Defects in GM2AP are the underlying causes for AB Variant of GM2 Gangliosidosis characterized by lysosomal accumulation of undegraded GM2 in neurons, fibroblasts and in several tissues of affected patients. Therefore, the study of SAPs is relevant to human health. In 1996 we discovered that prosaposin was sorted in the Golgi apparatus and transported to the lysosomes in a mannose-6-phosphate independent manner. Later we identified the internal amino acid sequence of prosaposin involved in this process and such a study suggested the existence of a lysosomal alternative receptor.

Recently, we have identified sortilin to be this novel lysosomal alternative receptor. We have demonstrated that sortilin is involved in the alternative sorting of the SAPs, prosaposin and GM2AP. We and other investigators showed that sortilin has a cytoplasmic GGA (Golgi-localized, γ-ear-containing, ARF-binding protein) binding motif similar to the M6P-R. GGA acts as adaptor proteins bridging the receptor and clathrin, a required step for the targeting of sorted proteins to lysosomes. With the identification of this novel receptor our laboratory has taken the lead in the study of lysosomal targeting of soluble proteins and our goal is to unfold the important clinical implications of this discovery. Although this alternative receptor was initially implicated in the sorting and trafficking of sphingolipid activator proteins, we have recently found that sortilin is also involved in the targeting of several lysosomal hydrolases including cathepsin H, cathepsin D and acid sphingomyelinase. We have cloned the sortilin gene and analyzed its structure and inactivated this gene by homologous recombination.

Studies on Reproduction

During the past 5 years, in collaboration with Dr. Scott Argraves (Medical University of South Carolina), we have pioneered functional studies on the role of the LDL receptor-like related protein-2 (LRP-2/megalin) in the male reproductive system. We demonstrated for the first time that apoliprotein J is the major ligand of megalin in the epididymis and that both proteins may play a role in sperm maturation and sperm capacitation. In addition, we have identified in the sperm plasma membrane several proteins involved in cholesterol efflux, a process that is essential for fertilization.

Lab Personnel

  • Carlos R. Morales, Professor
  • Jibin Zeng, Research Assistant
  • Maryssa Canuel, Postdoctoral Fellow
  • Yuan Libin, Ph.D. Student
  • Xiaoyan Ni, Research Assistant

Selected Publications

Lysosomal Studies

Musunuru K., Morales C.R., Rader D.J. et al. (2010) From DNA sequence variant to lipoprotein phenotype at a novel cholesterol and myocardial infarction locus. Nature 466: 714-721

Zeng J., Morales C.R. 2009 The inactivation of the sortilin gene leads to a partial disruption of prosaposin trafficking to the lysosomes. Exp. Cell Res. 315: 3112-312

Yuan L., Morales C.R. 2009 A stretch of 17 Amino Acids in the Prosaposin C-Terminus is Critical for its Binding to Sortilin and Targeting to Lysosomes. J. Histochem. Cytochem. 58:287-300, 2010

Canuel M., Bhattacharyya N., Balbis A., Morales C.R. 2009 Sortilin and prosaposin localize to detergent-resistant membrane microdomains. Exp. Cell Res. 315: 240-247

Canuel M., Korkidakis A., Konnyu K., Morales C.R. 2008 Sortilin mediates the lysosomal targeting of cathepsins D and H. Biochem. Biophys. Res. Comm. 373: 292-297

Canuel M., Lefrancois S., Zeng J., Morales C.R. 2008 AP-1 and retromer play opposite roles in the trafficking of sortilin between the TGN and lysosomes. Biochem. Biophys. Res. Comm. 366: 724-730

Seyrantepe V., Canuel M., Zeng J., Landry L., Feng L., Durand S., Carpentier S., Gravel R.A., Michaud J., Marchesini S., Zwingmann C., Morales C.R., Levade T., Pshezhetsky A.V. 2008 Mice deficient in the Neu4 sialidase exhibit abnormal ganglioside catabolism and lysosomal storage. Hum. Mol. Genet. 17: 1556-1568

Ni X., C.R. Morales 2006 The trafficking of acid sphingomyelinase (ASM) to the lysosomes is mediated by sortilin and the mannose 6-phosphate receptor. Traffic. 7: 859-863

Lefrancois S., Canuel M., Zeng J. Morales C.R. 2005 Inactivation of sortilin (a novel lysosomal sorting receptor) by dominant negative competition and RNA interference. Biol. Proced. Online 7: 17-25

Hassan J.A., J. Zeng, N. Xiaoyan, C.R. Morales 2004 The trafficking of prosaposin (SGP-1) and GM2AP to the lysosomes of TM4 Sertoli cells is mediated by sortilin and monomeric adaptor proteins. Mol. Rep. Dev. 68:476-83

Zeng J., A.J. Hassan, C.R. Morales 2004 Study of the mouse sortilin gene. Effects of its transient silencing by RNA interference in TM4 Sertoli cells. Mol. Rep. Dev. 68: 469-475

Zhou D., C. Cantu III, Y. Sagiv, A.B. Kulkarni, X. Qi, D.J. Mahuran, C.R. Morales, G. Grabowski, K. Benlagha, P. Savage, A. Bendelac, L. Teyton 2004 Editing of CD1d bound-lipid antigens by endosomal lipid transfer proteins. Science 303: 523-527

Lefrancois S., J. Zeng, A. Hassan, C. Canuel, C.R. Morales 2003 The lysosomal trafficking of sphingolipid activator proteins (SAPs) is mediated by sortilin EMBO J. 22: 1-8

Reproductive Studies

Morales C.R., Marat A.L., Ni X., Smith B.T., Argraves W.S. 2008 ATP-Binding Cassette Transporters ABCA1, ABCA7 and ABCG1 in Mouse Spermatozoa. Biochem. Biophys. Res. Comm. 376: 472-477

Argraves S.W., C.R. Morales 2004 Uterine and oviduct expression of the cubilin, megalin, apolipoprotein J and apolipoprotein A-1. Mol. Rep. Dev. 69: 419-427