Protease Regulation: The Yin and Yang of Neural Development and Disease

Howard Hughes Medical Institute and Gene Expression Laboratory, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
Neuron (Impact Factor: 15.05). 10/2011; 72(1):9-21. DOI: 10.1016/j.neuron.2011.09.012
Source: PubMed


The formation, maintenance, and plasticity of neural circuits rely upon a complex interplay between progressive and regressive events. Increasingly, new functions are being identified for axon guidance molecules in the dynamic processes that occur within the embryonic and adult nervous system. The magnitude, duration, and spatial activity of axon guidance molecule signaling are precisely regulated by a variety of molecular mechanisms. Here we focus on recent progress in understanding the role of protease-mediated cleavage of guidance factors required for directional axon growth, with a particular emphasis on the role of metalloprotease and γ-secretase. Since axon guidance molecules have also been linked to neural degeneration and regeneration in adults, studies of guidance receptor proteolysis are beginning to define new relationships between neurodevelopment and neurodegeneration. These findings raise the possibility that the signaling checkpoints controlled by proteases could be useful targets to enhance regeneration.

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    • "Indeed, several cell surface receptors and proteins including Notch 1, ERBB4, Robo, N-cadherins, neuregulins, P75NTR, LRP1, APLP1, and APLP2, among others, are also cleaved by secretases . Secretase-mediated cleavage of these proteins results in the production of extracellular and intracellular fragments with unique physiological functions (De Strooper et al., 1999; Ni et al., 2001; Reiss et al., 2005; Scheinfeld et al., 2002; reviewed by Bai and Pfaff, 2011). The similarity of APP structure and processing with many of these receptors suggests that APP might also act as a cell surface receptor with specialized functions; however, natural physiological ligands for APP remain elusive. "
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    ABSTRACT: A role of amyloid β (Aβ) peptide aggregation and deposition in Alzheimer's disease (AD) pathogenesis is widely accepted. Significantly, abnormalities induced by aggregated Aβ have been linked to synaptic and neuritic degeneration, consistent with the "dying-back" pattern of degeneration that characterizes neurons affected in AD. However, molecular mechanisms underlying the toxic effect of aggregated Aβ remain elusive. In the last 2 decades, a variety of aggregated Aβ species have been identified and their toxic properties demonstrated in diverse experimental systems. Concurrently, specific Aβ assemblies have been shown to interact and misregulate a growing number of molecular effectors with diverse physiological functions. Such pleiotropic effects of aggregated Aβ posit a mayor challenge for the identification of the most cardinal Aβ effectors relevant to AD pathology. In this review, we discuss recent experimental evidence implicating amyloid β precursor protein (APP) as a molecular target for toxic Aβ assemblies. Based on a significant body of pathologic observations and experimental evidence, we propose a novel pathologic feed-forward mechanism linking Aβ aggregation to abnormalities in APP processing and function, which in turn would trigger the progressive loss of neuronal connectivity observed early in AD.
    Neurobiology of aging 05/2013; 34(11). DOI:10.1016/j.neurobiolaging.2013.04.021 · 5.01 Impact Factor
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    • "This is particularly true for a large class of membrane-bound proteases, referred to as sheddases, which mostly cleave single-span membrane proteins at the extracellular surface of cellular membranes. This process is termed as ectodomain shedding and is essential for the communication between cells (Reiss and Saftig, 2009; Bai and Pfaff, 2011; Lichtenthaler et al, 2011). Shedding is involved in various physiological and pathophysiological conditions, including Alzheimer's disease. "
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    ABSTRACT: Cell surface proteolysis is essential for communication between cells and results in the shedding of membrane-protein ectodomains. However, physiological substrates of the contributing proteases are largely unknown. We developed the secretome protein enrichment with click sugars (SPECS) method, which allows proteome-wide identification of shedding substrates and secreted proteins from primary cells, even in the presence of serum proteins. SPECS combines metabolic glycan labelling and click chemistry-mediated biotinylation and distinguishes between cellular and serum proteins. SPECS identified 34, mostly novel substrates of the Alzheimer protease BACE1 in primary neurons, making BACE1 a major sheddase in the nervous system. Selected BACE1 substrates-seizure-protein 6, L1, CHL1 and contactin-2-were validated in brains of BACE1 inhibitor-treated and BACE1 knock-out mice. For some substrates, BACE1 was the major sheddase, whereas for other substrates additional proteases contributed to total substrate shedding. The new substrates point to a central function of BACE1 in neurite outgrowth and synapse formation. SPECS is also suitable for quantitative secretome analyses of primary cells and may be used for the discovery of biomarkers secreted from tumour or stem cells.
    The EMBO Journal 06/2012; 31(14):3157-68. DOI:10.1038/emboj.2012.173 · 10.43 Impact Factor
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    • "The emerging evidence supporting a role for membrane associated proteases in axon guidance have focused on metalloproteases and γ-secretases in both invertebrate and vertebrate organisms23. To test the hypothesis that the membrane-associated protease BACE1 also plays a role in guiding axons in vivo, we analyzed the connectivity of OSNs in mice with only one or no BACE1 functional allele. "
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    ABSTRACT: The β-site amyloid precursor protein cleaving enzyme 1 (BACE1) is necessary to generate the Aβ peptide, which is implicated in Alzheimer's disease pathology. Studies show that the expression of BACE1 and its protease activity are tightly regulated, but the physiological function of BACE1 remains poorly understood. Recently, numerous axon guidance proteins were identified as potential substrates of BACE1. Here, we examined the consequences of loss of BACE1 function in a well-defined in vivo model system of axon guidance, mouse olfactory sensory neurons (OSNs). The BACE1 protein resides predominantly in proximal segment and the termini of OSN axons, and the expression of BACE1 inversely correlates with odor-evoked neural activity. The precision of targeting of OSN axons is disturbed in both BACE1 null and, surprisingly, in BACE1 heterozygous mice. We propose that BACE1 cleavage of axon guidance proteins is essential to maintain the connectivity of OSNs in vivo.
    Scientific Reports 01/2012; 2:231. DOI:10.1038/srep00231 · 5.58 Impact Factor
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