The role of the neural cell adhesion molecule CHL1 in modulation of the chaperone activity of the trimeric protein complex of Hsc70/CSP/SGT in synapses
Final Report Abstract
In this project we have analyzed a novel role of the cell adhesion molecule CHL1 in the maintenance of synapses via regulation of the activity of the synaptic chaperone complexes. We have found that the intracellular domain of CHL1 directly associate with the presynaptic chaperones and induces formation of several different complexes with different refolding activity towards several presynaptic proteins involved in synaptic vesicle exocytosis. We have also shown that disruption of these complexes by CHL1 deficiency results in impaired synaptic vesicle recycling. We have also shown that levels of CHL1 at the neuronal cell surface are dynapmically regulated by ligand induced endocytosis of CHL1. We have analyzed the molecular mechanisms of CHL1 endocytosis and found that they involve redistribution of CHL1 to lipid-enriched microdomains, Ca2+ influx and disruption of the association of CHL1 with the sub-membrane spectrin cytoskeleton. We have also found that excessive levels of CHL1 play an inhibitory role in regulation of axonal growth in neurons. Mutations in CHL1 lead to psychiatric disorders in humans, which are known to be linked to the abnormal neuronal development and malfunctioning of synapses in the brain. The results obtained in this work explain the molecular mechanisms of the disorders linked to mutations in CHL1, and can be used to design novel therapeutic drugs that will be used to treat such disorders. The results also improve our understanding of how the normal brain works.
Publications
- 2007. Glial scar expression of CHL1, the close homolog of the adhesion molecule L1, limits recovery after spinal cord injury. J Neurosci. 27(27):7222-33
Jakovcevski I, Wu J, Karl N, Leshchyns'ka I, Sytnyk V, Chen J, Irintchev A, Schachner M
- 2010. CHL1 is a selective organizer of the presynaptic machinery chaperoning the SNARE complex. PLoS One. 5(8):e12018
Andreyeva A, Leshchyns'ka I, Knepper M, Betzel C, Redecke L, Sytnyk V, Schachner M
- 2012. Lipid raft-dependent endocytosis of close homolog of adhesion molecule L1 (CHL1) promotes neuritogenesis. J Biol Chem. 287(53):44447-63
Tian N, Leshchyns'ka I, Welch JH, Diakowski W, Yang H, Schachner M, Sytnyk V
(See online at https://doi.org/10.1074/jbc.M112.394973)
