Disturbance of cerebellar synaptic maturation in mutant mice lacking BSRPs, a novel brain‐specific receptor‐like protein family

Abstract

By DNA cloning, we have identified the BSRP (brainspecific receptor-like proteins) family of three members in mammalian genomes. BSRPs were predominantly expressed in the soma and dendrites of neurons and localized in the endoplasmic reticulum (ER). Expression levels of BSRPs seemed to fluctuate greatly during postnatal cerebellar maturation. Triple-knockout mice lacking BSRP members exhibited motor discoordination, and Purkinje cells (PCs) were often innervated by multiple climbing fibers with different neuronal origins in the mutant cerebellum. Moreover, the phosphorylation levels of protein kinase Ca (PKCa) were significantly downregulated in the mutant cerebellum. Because cerebellar maturation and plasticity require metabotropic glutamate receptor signaling and resulting PKC activation, BSRPs are likely involved in ER functions supporting PKCa activation in PCs.

Cathepsin D and its newly identified transport receptor SEZ6L2 can modulate neurite outgrowth

“…S1D). Finally, in accordance with the published report of a predominant neuronal expression of SEZ6L2 (Miyazaki et al, 2006), we mainly detected SEZ6L2 in the mouse brain, and found that it was expressed endogenously in a mouse neuroblastoma cell line (N1E-115) (Fig. 1B).…”

“…This finding, coupled with neuron-specific expression of SEZ6L2 (Miyazaki et al, 2006), and with the reported observation that cathepsin D binding to LRP1 in fibroblasts promotes their outgrowth (Beaujouin et al, 2010), suggest a cell type specificity of some alternatives to the Man-6-P transport pathways and linkage of these pathways to specific cellular processes.…”

“…prevent it, remain unclear but might involve protein kinase C (PKC). The phosphorylation of PKCα is decreased in triple Sez6, Sez6l2 and Sez6l2 knockout mice (Miyazaki et al, 2006) and several findings support a role for PKC activity in the regulation of neuronal differentiation (Larsson, 2006). For example, it has been reported that the activation of PKC in SH-SY-5Y neuroblastoma cells inhibits neurite outgrowth induced by serum deprivation or calpain inhibition (Shea et al, 1995), whereas PKC inhibition in Neuro2-a cells induces their differentiation (Miñana et al, 1990).…”

“…Anti-SEZ6L2 antibodies have also been detected in a patient suffering from cerebellar ataxia and retinopathy (Yaguchi et al, 2014). Finally, it has been reported that mice deficient for all three SEZ6 members (Miyazaki et al, 2006) or for SEZ6 alone (Gunnersen et al, 2007) suffer from motor discoordination, cognitive defects and abnormal neuronal innervation, and that SEZ6 controls neuronal branching (Gunnersen et al, 2007). However, the roles of SEZ6L and SEZ6L2 are less well known, and the molecular mechanisms that mediate the action(s) of SEZ6 proteins in the brain are unclear.…”

Untitled

“…Proteins of the Seizure protein 6 (Sez6) family are abundant in neurons and are localized to the somatodendritic compartment of these highly polarised cells (Gunnersen et al, 2007;Miyazaki et al, 2006). Two recent studies (Kuhn et al, 2012;Pigoni et al, 2016) highlight the important role of the Alzheimer's disease (AD)-linked aspartyl-protease β-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1) in the regulation of Sez6 and Sez6-like (Sez6L), influencing their sub-cellular distribution and, presumably, their function.…”