Abstract
Cystatin B (CSTB) is a ubiquitous protein belonging to a superfamily of protease inhibitors. CSTB may play a critical role in brain physiology because its mutations cause progressive myoclonic epilepsy-1A (EPM1A), the most common form of progressive myoclonic epilepsy. However, the molecular mechanisms underlying the role of CSTB in the central nervous system (CNS) are largely unknown. To investigate the possible involvement of CSTB in the synaptic plasticity, we analyzed its expression in synaptosomes as a model system in studying the physiology of the synaptic regions of the CNS. We found that CSTB is not only present in the synaptosomes isolated from rat and mouse brain cortex, but also secreted into the medium in a depolarization-controlled manner. In addition, using biorthogonal noncanonical amino acid tagging (BONCAT) procedure, we demonstrated, for the first time, that CSTB is locally synthesized in the synaptosomes. The synaptic localization of CSTB was confirmed in a human 3D model of cortical development, namely cerebral organoids. Altogether, these results suggest that CSTB may play a role in the brain plasticity and open a new perspective in studying the involvement of CSTB deregulation in neurodegenerative and neuropsychiatric diseases.
Highlights
Cystatin B (CSTB) is an inhibitor of the cathepsin family of proteases, widely expressed in most cell types and tissues
When the distribution of CSTB in the synaptic compartment was examined (Figures 1A,B), it was evident that CSTB was present in rat synaptosomal fractions it was more abundant in the homogenate, in keeping with its well-known cytosolic localization
We demonstrated, for the first time, that CSTB is present in the synaptic region of the neuron
Summary
Cystatin B (CSTB) is an inhibitor of the cathepsin family of proteases, widely expressed in most cell types and tissues. The cell type-specific expression of CSTB in developing cerebellum suggests that the expression of this protein is finely regulated (Riccio et al, 2005). It has been proposed that CSTB is involved in the mechanisms preventing cerebral apoptosis (Pennacchio et al, 1998) and protecting neurons from oxidative stress. Consistent with this hypothesis, CSTB knock-out (KO) mice display signs of oxidative stress, progressive ataxia, and neuronal death (Lehtinen et al, 2009). CSTB has a high capacity to interact with the superoxide dismutase 1 (SOD-1), a protein that has an important function in preventing the accumulation of reactive oxygen species (ROS; Ulbrich et al, 2014)
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