During development of the central and peripheral nervous systems, neurite extension mediated via glial-cell-line-derived neurotrophic factor (GDNF) and its receptor RET is critical for neuronal differentiation. In the present study, we investigated the role of the RET substrate Dok-4 in neurite outgrowth induced by the GDNF/RET signaling pathway. In TGW neuroblastoma cells, which endogenously express both RET and Dok-4, depletion of Dok-4 through treatment with small interfering RNA resulted in a marked decrease in GDNF-stimulated neurite outgrowth. By contrast, exogenous expression of wild-type Dok-4 induced sustained p44/42 mitogen-activated protein kinase (ERK1/2) activation and enhanced neurite outgrowth. Expression of Dok-4 mutants in which the tyrosine residues at codons 187, 220 and 270, conserved between Dok-4, -5, and -6, were each replaced with a phenylalanine inhibited sustained ERK1/2 activation and neurite outgrowth. We also found that Dok-4 induced a significant activation of the small G protein Rap1 and that expression of a dominant active Rap1 mutant restored neurite outgrowth in Dok-4-depleted cells. By contrast, expression of a dominant negative Rap1 mutant impaired GDNF-stimulated neurite outgrowth from TGW cells. Finally, we found that neurite formation in cultured rat hippocampal neurons was enhanced by the expression of Dok-4. Together, our results suggest that Dok-4, through activation of the Rap1-ERK1/2 pathway, regulates GDNF-mediated neurite outgrowth during neuronal development.
Photoabsorption cross sections for the ns' and nd' autoionizing Rydberg series of Xe have been measured with a resolution of 7.4 m\AA{} using a high-resolution spectrometer and synchrotron radiation. The cross sections are parametrized with the aid of a line-shape formula that is based on the multichannel-quantum-defect theory and has a form analogous to Fano's resonance formula and are compared in detail with theoretical predictions available in the literature.
Although oculomotor nerve palsy, which is common in diabetes, is considered an ischemic mononeuropathy, the susceptibility of the oculomotor nerve to ischemic insult is not well understood. We analyzed the density of endoneurial microvessels of the oculomotor nerve and compared it with that of the sural nerve in non-diabetic patients. The mean vascular density of the oculomotor nerve (23 ± 8.4/mm2) was significantly smaller than that of the sural nerves (60 ± 29/mm2). The spatial distribution of the microvessels in the inner half (25.3 ± 6.7) was not different from that in the outer half (22.7 ± 9.4) in the oculomotor nerve. The lower density of microvessels in the oculomotor nerve might contribute to its susceptibility to ischemia.
Mutations in small heat shock protein beta-1 (HspB1) have been linked to Charcot-Marie-Tooth (CMT) disease type 2F and distal hereditary motor neuropathy type 2B. Only four cases with HSPB1 mutations have been reported to date in Japan. In this study between April 2007 and October 2014, we conducted gene panel sequencing in a case series of 1,030 patients with inherited peripheral neuropathies (IPNs) using DNA microarray, targeted resequencing, and whole-exome sequencing. We identified HSPB1 variants in 1.3% (13 of 1,030) of the patients with IPNs, who exhibited a male predominance. Based on neurological and electrophysiological findings, seven patients were diagnosed with CMT disease type 2F, whereas the remaining six patients were diagnosed with distal hereditary motor neuropathy type 2B. P39L, R127W, S135C, R140G, K141Q, T151I, and P182A mutations identified in 12 patients were described previously, whereas a novel K123* variant with unknown significance was found in 1 patient. Diabetes and impaired glucose tolerance were detected in 6 of the 13 patients. Our findings suggest that HSPB1 mutations result in two phenotypes of inherited neuropathies and extend the phenotypic spectrum of HSPB1-related disorders.
Monday, April 27April 14, 2020Free AccessLong-read Sequencing Identifies GGC Repeat Expansions in NOTCH2NLC as the Cause of Neuronal Intranuclear Inclusion Disease (2832)Jun Sone, Satomi Mitsuhashi, Atsushi Fujita, Hiroshi Takashima, Hiroshi Sugiyama, Yoshihisa Takiyama, Kengo Maeda, Fumiaki Tanaka, Yasushi Iwasaki, Mari Yoshida, Naomichi Matsumoto, and Gen SobueAuthors Info & AffiliationsApril 14, 2020 issue94 (15_supplement)https://doi.org/10.1212/WNL.94.15_supplement.2832 Letters to the Editor
Since the worldwide spread of the novel influenza type A virus in 2009, trivalent vaccines against H1N1 (pandemic) 09 and seasonal influenza have been used. We describe a 33-year-old woman who presented with hypoesthesia below the Th7 level fifteen days after vaccination without any preceding infection. Cerebrospinal fluid showed an increased level of myelin basic protein and positive oligoclonal IgG bands. Magnetic resonance imaging revealed disseminated lesions in the brain and thoracic cord. Steroid therapy improved her symptoms. She was diagnosed as having acute disseminated encephalomyelitis (ADEM) possibly related to the vaccination. As a potential adverse effect of the influenza vaccine, in addition to Guillain-Barré syndrome, ADEM should also be recognized.
It has not been fully examined whether angiotensin II receptor blocker is superior to calcium channel blocker to reduce cardiovascular events in hypertensive patients with glucose intolerance. A prospective, open-labeled, randomized, controlled trial was conducted for Japanese hypertensive patients with type 2 diabetes mellitus or impaired glucose tolerance. A total of 1150 patients (women: 34%; mean age: 63 years; diabetes mellitus: 82%) were randomly assigned to receive either valsartan- or amlodipine-based antihypertensive treatment. Primary outcome was a composite of acute myocardial infarction, stroke, coronary revascularization, admission attributed to heart failure, or sudden cardiac death. Blood pressure was 145/82 and 144/81 mm Hg, and glycosylated hemoglobin was 7.0% and 6.9% at baseline in the valsartan group and the amlodipine group, respectively. Both of them were equally controlled between the 2 groups during the study. The median follow-up period was 3.2 years, and primary outcome had occurred in 54 patients in the valsartan group and 56 in the amlodipine group (hazard ratio: 0.97 [95% CI: 0.66–1.40]; P =0.85). Patients in the valsartan group had a significantly lower incidence of heart failure than in the amlodipine group (hazard ratio: 0.20 [95% CI: 0.06–0.69]; P =0.01). Other components and all-cause mortality were not significantly different between the 2 groups. Composite cardiovascular outcomes were comparable between the valsartan- and amlodipine-based treatments in Japanese hypertensive patients with glucose intolerance. Admission because of heart failure was significantly less in the valsartan group.
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