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The Neurotrypsin/agrin System-towards a Molecular Foundation of its fundamental Role for Intellectual Development and Function
Sonderegger Peter
Department of Biochemistry, University of Zürich, Switzerland
The synaptic serine peptidase neurotrypsin is essential for the development of higher brain functions, as a deletion in the neurotrypsin gene of humans causes severe intellectual disability.
The so far sole proteolytic target identified for neurotrypsin is the extracellular matrix proteoglycan agrin. Agrin has been extensively characterized for its role in the formation and maintenance of the neuromuscular junction. However, recent analyses demonstrated that agrin plays also an essential role in the formation and re-organization of neuronal circuits in the central nervous system.
Our work demonstrated the activity-dependent exocytosis of neurotrypsin from presynaptic nerve terminals. Secreted neurotrypsin, however, is proteolytically inactive. It can cleaveagrin only after conversion into the active peptidase by an NMDA receptor-dependent postsynaptic mechanism. Thus, the neurotrypsin/agrin system acts as a coincidence detector of pre-and postsynaptic activity.
Because we observed that neurotrypsin lingersin the synaptic extracellular compartment after its exocytosis and that neurotrypsin-dependent agrin cleavage is mainly perisynaptic, we studied the binding of neurotrypsin to extracellular macromolecular components. We found binding of neurotrypsin to the glycosaminoglycan side chains of agrin, which in turn enhanced the activation of neurotrypsin by proprotein convertases and resulted in enhanced agrin cleavage. Binding of neurotrypsin to cell surface glycosaminoglycans prevents its diffusion and locallyrestricts its conversion from the zymogen to the active peptidase. This contains the proteolytic action of neurotrypsin within a narrow range around the secreting synapse.
As the resulting 22-kD fragment of agrin induces dendritic filopodia, which are considered as precursors of new synapses, the synaptic secretion of neurotrypsin defines a region of potential synapse formation at synapses with correlated pre-and post-synaptic activity. Thus, the neurotrypsin/agrin system is instrumental for the synapse-centred initiation of highly specific reorganizations of neuronal circuits. Because these processes are fundamental for normal intellectual development and function, the lack of functional neurotrypsin results in intellectual disability.
Acknowledgment：
This work was supported by grants of the Swiss National Science Foundation and the Olga Mayenfisch Foundation. | | | |
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