CHL1 Is a Selective Organizer of the Presynaptic Machinery Chaperoning the SNARE Complex

Aksana Andreyeva,Lars Redecke,Christian Betzel,Michael Knepper,Vladimir Sytnyk,Iryna Leshchyns'Ka,Melitta Schachner,Christoph Kleinschnitz

doi:10.1371/journal.pone.0012018

Abstract

Proteins constituting the presynaptic machinery of vesicle release undergo substantial conformational changes during the process of exocytosis. While changes in the conformation make proteins vulnerable to aggregation and degradation, little is known about synaptic chaperones which counteract these processes. We show that the cell adhesion molecule CHL1 directly interacts with and regulates the activity of the synaptic chaperones Hsc70, CSP and αSGT. CHL1, Hsc70, CSP and αSGT form predominantly CHL1/Hsc70/αSGT and CHL1/CSP complexes in synapses. Among the various complexes formed by CHL1, Hsc70, CSP and αSGT, SNAP25 and VAMP2 induce chaperone activity only in CHL1/Hsc70/αSGT and CHL1/CSP complexes, respectively, indicating a remarkable selectivity of a presynaptic chaperone activity for proteins of the exocytotic machinery. In mice with genetic ablation of CHL1, chaperone activity in synapses is reduced and the machinery for synaptic vesicle exocytosis and, in particular, the SNARE complex is unable to sustain prolonged synaptic activity. Thus, we reveal a novel role for a cell adhesion molecule in selective activation of the presynaptic chaperone machinery.

Highlights

Close homologue of L1 (CHL1), a cell adhesion molecule of the immunoglobulin superfamily, regulates migration and differentiation of neurons during ontogenetic development, and enhances neuronal survival [1,2,3,4,5,6]
We show that CHL1 associates with presynaptic chaperones in the CHL1/Hsc70/ aSGT and CHL1/cysteine string protein (CSP) complexes, the activities of which are directed towards the SNARE complex
We describe a novel role for CHL1 as a co-chaperone in the presynaptic chaperone machinery consisting of Hsc70, CSP and aSGT

Summary

Introduction

Close homologue of L1 (CHL1), a cell adhesion molecule of the immunoglobulin superfamily, regulates migration and differentiation of neurons during ontogenetic development, and enhances neuronal survival [1,2,3,4,5,6]. Prepulse inhibition of the acoustic startle response, a measure of the ability of the central nervous system to gate the flow of sensorimotor information, and working memory, which are reduced in schizophrenic patients, are reduced in CHL1 constitutively and conditionally deficient mice [8,10]. It remains unclear, how mutations in CHL1 contribute to the development of schizophrenia, the symptoms of which appear only in adulthood, apparently weakening a direct link to CHL1-related abnormalities in ontogenetic brain development and raising the question whether CHL1 may relate more directly to synaptic function

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