Role of IGF-II/M6P receptor in the regulation of brain function

  • Author / Creator
    Amritraj, Asha
  • Insulin-like growth factor-II/mannose-6-phosphate (IGF-II/M6P) receptor is a single trans-membrane glycoprotein that is widely but selectively distributed throughout the central nervous system (CNS). IGF-II/M6P receptor is involved in the trafficking of M6P-containing lysosomal enzymes from the trans-Golgi network to the endosomes and lysosomes. A subset of the receptors that are localized on the cell surface promotes internalization and subsequent degradation or activation of extracellular IGF-II and other M6P-bearing ligands. At present, very little is known about the significance of the receptor and/or lysosomal enzymes trafficked by this receptor in the functioning of the CNS. Results from this thesis indicate that in the normal brain, IGF-II/M6P receptors are associated with G protein and localized, in part, on detergent-resistant membranes. Following stimulation with an IGF-II analogue, Leu27IGF-II, the receptors are translocated to the detergent soluble fraction along with -arrestin and may lead to the stimulation of extracellular-signal related kinase 1/2 via a pertussis toxin-dependent pathway. Activation of IGF-II/M6P receptors by Leu27IGF-II also leads to a decrease in GABA release from the hippocampus and cortical regions of the brain. Subsequently, we analyzed the role of the IGF-II receptor and the lysosomal enzymes cathepsins B and D in animal models of Alzheimer's disease (AD) and Niemann Pick type C (NPC) disorder. In transgenic mouse models of AD that do not exhibit neuronal loss, the IGF-II/M6P receptor and the lysosomal enzyme levels are up-regulated and localized in some -amyloid (A)-containing neuritic plaques in the hippocampal and cortical regions of the brain. These results may represent an altered functioning of the endosomal-lysosomal system to protect neurons against increased levels of A peptide. Using the Npc1-/- mouse, a well established model of NPC1 pathology, we have shown that expression, but not levels, of the IGF-II/M6P receptors is altered both in the non-vulnerable hippocampal and vulnerable cerebellar regions of the brain. The levels and activity of lysosomal enzymes catepsins B or D, on the other hand, were increased more predominently in the cerebellum than the hippocampus of Npc1-/- mice accompanied by elevated cytosolic levels of cathepsins, cytochrome c and Bax2, suggesting a potential role for these enzymes in the degeneration of neuron. This is partly substantiated by the observation that degeneration of cultured mouse cortical neurons treated with U18666A, which induces an NPC1-like phenotype at the cellular level, can be attenuated by inhibition of the lysosomal enzyme activity. Furthermore, down-regulation of cathepsin D levels by siRNA treatment was found to render cultured N2a cells somewhat resistant to U18666A-induced toxicity. Additionally, we have shown that cathepsin D released from U18666A-treated cultured neurons or application of exogenous enzyme can induce neurotoxicity. These results suggest that increased levels/activity and altered subcellular distribution of cathepsins may be associated with the underlying cause of neuronal vulnerability in Npc1-/- brains and that their inhibitors may have therapeutic potential in attenuating NPC pathology. Collectively, these results indicate that IGF-II/M6P receptors in the brain could play a multifunctional role, including in transmembrane signal transduction, modulation of neurotransmitter release and the adaptive response that follows neuronal injury and/or toxicity observed in various models of neurodegenerative disorders.

  • Subjects / Keywords
  • Graduation date
  • Type of Item
  • Degree
    Doctor of Philosophy
  • DOI
  • License
    This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.
  • Language
  • Institution
    University of Alberta
  • Degree level
  • Department
    • Department of Psychiatry
  • Supervisor / co-supervisor and their department(s)
    • Kar, Satyabrata (Medicine and Psychiatry)
  • Examining committee members and their departments
    • Baker, Glen B. (Psychiatry)
    • Levesque, Georges (Neuroscience, University of Laval)
    • Le Mellédo, Jean-Michel (Psychiatry)
    • Westaway, David (Medicine)
    • Kar, Satyabrata (Medicine and Psychiatry)