L-Dihydroxyphenylalanine Methyl Ester is a Potent Competitive Antagonist of the L-Dihydroxyphenylalanine-lnduced Facilitation of the Evoked Release of Endogenous Norepinephrine from Rat Hypothalamic Slices'

ABSTRACT 46

Phosphatidylinositol 4-phosphate 5-kinase β regulates growth cone morphology and Semaphorin 3A-triggered growth cone collapse in mouse dorsal root ganglion neurons

Growth cone motility and morphology, which are critical for axon guidance, are controlled through intracellular events such as actin cytoskeletal reorganization and vesicular trafficking. The membrane phospholipid phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] has been implicated in regulation of these cellular processes in a diverse range of cell types. The main kinases involved in the production of PI(4,5)P2 are the type I phosphatidylinositol 4-phosphate 5-kinase (PIP5K) family, which consist of three isozymes, α, β and γ. Here, we demonstrate the involvement of PIP5Kβ in growth cone dynamics. Overexpression of a lipid kinase-deficient mutant of PIP5Kβ (PIP5Kβ-KD) in mouse dorsal root ganglion (DRG) neurons stimulated axon elongation and increased growth cone size, whereas wild-type PIP5Kβ tended to show opposite effects. Furthermore, PIP5Kβ-KD inhibited growth cone collapse of DRG neurons induced by semaphorin 3A (Sema3A). These results provide evidence that PIP5Kβ negatively regulates axon elongation and growth cone size and is involved in the cellular signaling pathway for Sema3A-triggered repulsion in DRG neurons

CRMP5 (Collapsin Response Mediator Protein 5) Regulates Dendritic Development and Synaptic Plasticity in the Cerebellar Purkinje Cells

Collapsin response mediator protein 5 (CRMP5) is one of the CRMP members that expresses abundantly in the developing brain. To examine the in vivo function of CRMP5, we generated crmp5-deficient (crmp5(-/-)) mice. Anti-calbindin immunofluorescence studies of crmp5(-/-) mice revealed aberrant dendrite morphology; specifically, a decrease in the size of soma and diameter of primary dendrite of the cerebellar Purkinje cells at postnatal day 21 (P21) and P28, but not at P14. Coincidentally, CRMP5 is detected in Purkinje cells at P21 and P28 from crmp5(+/-) mice. In cerebellar slices of crmp5(-/-) mice, the induction of long-term depression of excitatory synaptic transmission between parallel fibers and Purkinje cells was deficient. Given that brain-derived neurotrophic factor (BDNF) plays major roles in dendritic development, we tried to elucidate the possible roles of CRMP5 in BDNF signaling. The effect of BDNF to induce dendritic branching was markedly attenuated in cultured crmp5(-/-) neurons. Furthermore, CRMP5 was tyrosine phosphorylated when coexpressed with neurotrophic tyrosine kinase receptor type 2 (TrkB), a receptor for BDNF, in HEK293T cells. These findings suggest that CRMP5 is involved in the development, maintenance and synaptic plasticity of Purkinje cells

Effects of prior osteoporosis treatment on early treatment response of romosozumab in patients with postmenopausal osteoporosis

Purpose: To investigate the effects of prior treatment and the predictors of early treatment response to romosozumab (ROMO) in patients with postmenopausal osteoporosis. Methods: In this prospective, observational, multicenter study, 130 treatment-naïve patients (Naïve; n = 37) or patients previously treated with bisphosphonates (BP; n = 33), denosumab (DMAb; n = 45), or teriparatide (TPTD; n = 15) (age, 75.0 years; T-scores of the lumbar spine [LS] −3.2 and femoral neck [FN] −2.9) were switched to ROMO based on their physician's decision. Bone mineral density (BMD) and serum bone turnover markers were evaluated for six months. Results: At six months, LS BMD changes were 13.6%, 7.5%, 3.6%, and 8.7% (P <.001 between groups) and FN BMD changes were 4.2%, 0.4%, 1.6%, and 1.5% (P =.16 between groups) for Naïve, BP, DMAb, and TPTD groups, respectively. Changes in N-terminal type I procollagen propeptide (PINP; μg/L) levels from baseline → one month were 72.7 → 139.0, 33.5 → 85.4, 30.4 → 54.3, and 98.4 → 107.4, and those of isoform 5b of tartrate-resistant acid phosphatase (TRACP-5b) (mU/dL) were 474.7 → 270.2, 277.3 → 203.7, 220.3 → 242.0, and 454.1 → 313.0 for Naïve, BP, DMAb, and TPTD groups, respectively. Multivariate regression analysis revealed that significant predictors of LS BMD change at six months were prior treatment difference (r = −3.1, P =.0027) and TRACP-5b percentage change (r = −2.8, P =.0071) and PINP value at one month (r = 3.2, P =.0021). Conclusion: Early effects of ROMO on the increase in LS BMD are significantly affected by the difference of prior treatment and are predicted by the early change in bone turnover markers. Mini abstract: Early effects of ROMO on the increase in LS BMD at six months is significantly affected by the difference of prior treatment and also predicted by the early change of bone turnover markers in patients with postmenopausal osteoporosis.Ebina K., Hirao M., Tsuboi H., et al. Effects of prior osteoporosis treatment on early treatment response of romosozumab in patients with postmenopausal osteoporosis. Bone 140, 115574 (2020); https://doi.org/10.1016/j.bone.2020.115574

Effects of prior osteoporosis treatment on 12-month treatment response of romosozumab in patients with postmenopausal osteoporosis

Objectives: To investigate the effects of prior treatment and determine the predictors of a 12-month treatment response of romosozumab (ROMO) in 148 patients with postmenopausal osteoporosis. Methods: In this prospective, observational, and multicenter study, treatment naïve patients (Naïve; n = 50) or patients previously treated with bisphosphonates (BP; n = 37) or denosumab (DMAb; n = 45) or teriparatide (TPTD; n = 16) (mean age, 75.0 years; T-scores of the lumbar spine [LS] −3.2 and total hip [TH] −2.6) were switched to ROMO due to insufficient effects of prior treatment. Bone mineral density (BMD) and serum bone turnover markers were evaluated for 12 months. Results: At 12 months, changes in LS BMD were Naïve (18.2%), BP (10.2%), DMAb (6.4%), and TPTD (11.2%) (P < 0.001 between groups) and changes in TH BMD were Naïve (5.6%), BP (3.3%), DMAb (0.6%), and TPTD (4.4%) (P < 0.01 between groups), respectively. In all groups, the LS BMD significantly increased from baseline at 6 and 12 months, although only the DMAb group failed to obtain a significant increase in TH BMD during 12-month treatment. Mean values of N-terminal type I procollagen propeptide (PINP; μg/L) from baseline → 1 month → 12 months were Naïve (67.9 → 134.1 → 51.0), BP (32. 2 → 81.7 → 40.9), DMAb (30.4 → 56.2 → 75.3), and TPTD (97.4 → 105.1 → 37.1), and those of isoform 5b of tartrate-resistant acid phosphatase (TRACP-5b; mU/dL) were Naïve (500.4 → 283.8 → 267.1), BP (273.4 → 203.1 → 242.0), DMAb (220.3 → 246.1 → 304.8), and TPTD (446.6 → 305.1 → 235.7), respectively. Multiple regression analysis revealed that the significant predictors of BMD change at 12 months were difference of prior treatment (r = −2.8, P < 0.001) and value of PINP at 1 month (r = 0.04, P < 0.01) for LS, and difference of prior treatment (r = −1.3, P < 0.05) and percentage change of TRACP-5b at 1 month (r = −0.06, P < 0.05) for TH. Conclusions: The early effects of ROMO on LS and TH BMD increase at 12 months were significantly affected by the difference of prior treatment and are predicted by the early change in bone turnover markers.Ebina K., Tsuboi H., Nagayama Y., et al. Effects of prior osteoporosis treatment on 12-month treatment response of romosozumab in patients with postmenopausal osteoporosis. Joint Bone Spine 88, 105219 (2021); https://doi.org/10.1016/j.jbspin.2021.105219

Collapsin response mediator protein 1 mediates Reelin signaling in cortical neuronal migration

Collapsin response mediator protein 1 ( CRMP1) is one of the CRMP family members that mediates signal transduction of axon guidance molecules. Here, we show evidence that CRMP1 is involved in Reelin ( Reln) signaling to regulate neuronal migration in the cerebral cortex. In crmp1(-/-) mice, radial migration of cortical neurons was retarded. This phenotype was not observed in the sema3A(-/-) and crmp1(+/+); sema3A(+/+) cortices. However, CRMP1 was colocalized with disabled- 1 ( Dab1), an adaptor protein in Reln signaling. In the Reln(rl/rl) cortex, CRMP1 and Dab1 were expressed at a higher level, yet tyrosine phosphorylated at a lower level. Loss of crmp1 in a dab1 heterozygous background led to the disruption of hippocampal lamination, a Reeler- like phenotype. In addition to axon guidance, CRMP1 regulates neuronal migration by mediating Reln signaling

A seven-transmembrane receptor that mediates avoidance response to dihydrocaffeic acid, a water-soluble repellent in Caenorhabditis elegans

The ability to detect harmful chemicals rapidly is essential for the survival of all animals. In Caenorhabditis elegans (C. elegans), repellents trigger an avoidance response, causing animals to move away from repellents. Dihydrocaffeic acid (DHCA) is a water-soluble repellent and nonflavonoid catecholic compound that can be found in plant products. Using a Xenopus laevis (X. laevis) oocyte expression system, we identified a candidate dihydrocaffeic acid receptor (DCAR), DCAR-1. DCAR-1 is a novel seven-transmembrane protein that is expressed in the ASH avoidance sensory neurons of C. elegans. dcar-1 mutant animals are defective in avoidance response to DHCA, and cell-specific expression of dcar-1 in the ASH neurons of dcar-1 mutant animals rescued the defect in avoidance response to DHCA. Our findings identify DCAR-1 as the first seven-transmembrane receptor required for avoidance of a water-soluble repellent, DHCA, in C. elegans

Identification and structural analysis of C-terminally truncated collapsin response mediator protein-2 in a murine model of prion diseases

<p>Abstract</p> <p>Background</p> <p>Prion diseases are fatal neurodegenerative disorders that accompany an accumulation of the disease-associated form(s) of prion protein (PrP^Sc) in the central nervous system. The neuropathological changes in the brain begin with focal deposits of PrP^Sc, followed by pathomorphological abnormalities of axon terminal degeneration, synaptic loss, atrophy of dendritic trees, and eventual neuronal cell death in the lesions. However, the underlying molecular basis for these neuropathogenic abnormalities is not fully understood.</p> <p>Results</p> <p>In a proteomic analysis of soluble proteins in the brains of mice challenged intracerebrally with scrapie prion (Obihiro I strain), we found that the amount of the full-length form of collapsin response mediator protein-2 (CRMP-2; 61 kDa) decreased in the late stages of the disease, while the amount of its truncated form (56 kDa) increased to comparable levels observed for the full-length form. Detailed analysis by liquid chromatography-electrospray ionization-tandem mass spectrometry showed that the 56-kDa form (named CRMP-2-ΔC) lacked the sequence from serine⁵¹⁸to the C-terminus, including the C-terminal phosphorylation sites important for the regulation of axonal growth and axon-dendrite specification in developing neurons. The invariable size of the mRNA transcript in Northern blot analysis suggested that the truncation was due to post-translational proteolysis. By overexpression of CRMP-2-ΔC in primary cultured neurons, we observed the augmentation of the development of neurite branch tips to the same levels as for CRMP-2^T514A/T555A, a non-phosphorylated mimic of the full-length protein. This suggests that the increased level of CRMP-2-ΔC in the brain modulates the integrity of neurons, and may be involved in the pathogenesis of the neuronal abnormalities observed in the late stages of the disease.</p> <p>Conclusions</p> <p>We identified the presence of CRMP-2-ΔC in the brain of a murine model of prion disease. Of note, C-terminal truncations of CRMP-2 have been recently observed in models for neurodegenerative disorders such as ischemia, traumatic brain injury, and Wallerian degeneration. While the structural identity of CRMP-2-ΔC in those models remains unknown, the present study should provide clues to the molecular pathology of degenerating neurons in prion diseases in connection with other neurodegenerative disorders.</p