| 11097158 | The pro-inflammatory cytokine 14-3-3epsilon is a ligand of CD13 in cartilage. | Nefla M, etal., J Cell Sci. 2015 Sep 1;128(17):3250-62. doi: 10.1242/jcs.169573. Epub 2015 Jul 24. | Osteoarthritis is a whole-joint disease characterized by the progressive destruction of articular cartilage involving abnormal communication between subchondral bone and cartilage. Our team previously identified 14-3-3epsilon protein as a subchondral bone soluble mediator altering cartilage homeosta sis. The aim of this study was to investigate the involvement of CD13 (also known as aminopeptidase N, APN) in the chondrocyte response to 14-3-3epsilon. After identifying CD13 in chondrocytes, we knocked down CD13 with small interfering RNA (siRNA) and blocking antibodies in articular chondrocytes. 14-3-3epsilon-induced MMP-3 and MMP-13 was significantly reduced with CD13 knockdown, which suggests that it has a crucial role in 14-3-3epsilon signal transduction. Aminopeptidase N activity was identified in chondrocytes, but the activity was unchanged after stimulation with 14-3-3epsilon. Direct interaction between CD13 and 14-3-3epsilon was then demonstrated by surface plasmon resonance. Using labeled 14-3-3epsilon, we also found that 14-3-3epsilon binds to the surface of chondrocytes in a manner that is dependent on CD13. Taken together, these results suggest that 14-3-3epsilon might directly bind to CD13, which transmits its signal in chondrocytes to induce a catabolic phenotype similar to that observed in osteoarthritis. The 14-3-3epsilon-CD13 interaction could be a new therapeutic target in osteoarthritis. | 26208633 | 2015-06-01 |
| 598117298 | NEFL Pro22Arg mutation in Charcot-Marie-Tooth disease type 1. | Shin JS, etal., J Hum Genet. 2008;53(10):936-940. doi: 10.1007/s10038-008-0333-8. Epub 2008 Aug 29. | Charcot-Marie-Tooth disease (CMT) is classified into demyelinating neuropathy (CMT1) and axonal neuropathy (CMT2). Mutations in the neurofilament light chain polypeptide (NEFL) gene are present in CMT2E and CMT1F neuropathies. Two types of Pro22 mutations have b een previously reported: Pro22Ser in CMT2E with giant axons, and Pro22Thr in CMT1F. In this study, we identified another Pro22 mutation, Pro22Arg, in a Korean CMT1 family. An investigation to identify the clinical and pathological characteristics of the Pro22Arg revealed that it is associated with demyelinating neuropathy features in CMT1F. Histopathological findings showed onion bulb formations but no giant axons. It appears that the Pro22 mutations may influence not only the Thr-Pro phosphorylation site by proline-directed protein kinases but also other structural alteration of the NEFL protein in a different way. | 18758688 | 2008-12-01 |
| 11521610 | miR-25 promotes glioblastoma cell proliferation and invasion by directly targeting NEFL. | Peng G, etal., Mol Cell Biochem. 2015 Nov;409(1-2):103-11. doi: 10.1007/s11010-015-2516-x. Epub 2015 Jul 26. | Glioblastoma multiforme (GBM) is the most malignant and common brain tumor; it is aggressive growth pattern means that GBM patients face a poor prognosis even when receiving the best available treatment modalities. In recent years, an increasing number of reports suggest that the discovery of microR NAs (miRNAs) might provide a novel therapeutic target for human cancers, including GBM. One miRNA in particular, microRNA-25 (miR-25), is overexpressed in several cancers, wherein accumulating evidence indicates that it functions as an oncogene. However, the function of miR-25 in GBM has not been totally elucidated. In this study, we demonstrated that miR-25 was significantly up-regulated in astrocytoma tissues and glioblastoma cell lines. In vitro studies further demonstrated that overexpressed miR-25 was able to promote, while its antisense oligos inhibited cell proliferation and invasion in U251 cells. Moreover, we identified neurofilament light polypeptide (NEFL) as a novel target molecule of miR-25. Also of note was the fact that NEFL was down-regulated with increased levels of miR-25 expression in human astrocytoma clinical specimens. In addition, via the mTOR signaling pathway, NEFL-siRNA could significantly attenuate the inhibitory effects of knockdown miR-25 on the proliferation and invasion of U251 cells. Overall, our results showed an important role for miR-25 in regulating NEFL expression in GBM, and suggest that miR-25 could be a potential target for GBM treatment. | 26209061 | 2015-08-01 |
| 598120426 | Mutations in the neurofilament light chain gene (NEFL) cause early onset severe Charcot-Marie-Tooth disease. | Jordanova A, etal., Brain. 2003 Mar;126(Pt 3):590-7. doi: 10.1093/brain/awg059. | Neurofilament light chain polypeptide (NEFL) is one of the most abundant cytoskeletal components of the neuron. Mutations in the NEFL gene were recently reported as a cause for autosomal dominant Charcot-Marie-Tooth type 2E (CMT2E) linked to chromosome 8p21. In order to investigate the frequency and phenotypic consequences of NEFL mutations, we screened 323 patients with CMT or related peripheral neuropathies. We detected six disease associated missense mutations and one 3-bp in-frame deletion clustered in functionally defined domains of the NEFL protein. Patients have an early onset and often a severe clinical phenotype. Electrophysiological examination shows moderately to severely slowed nerve conduction velocities. We report the first nerve biopsy of a CMT patient with a de novo missense mutation in NEFL, and found an axonal pathology with axonal regeneration clusters and onion bulb formations. Our findings provide further evidence that the clinical variation observed in CMT depends on the gene mutated and the specific type of mutation, and we also suggest that NEFL mutations need to be considered in the molecular evaluation of patients with sporadic or dominantly inherited CMT. | 12566280 | 2003-03-01 |
| 11058509 | NEFL E396K mutation is associated with a novel dominant intermediate Charcot-Marie-Tooth disease phenotype. | Berciano J, etal., J Neurol. 2015 May;262(5):1289-300. doi: 10.1007/s00415-015-7709-4. Epub 2015 Apr 1. | The purpose of the study was to describe a pedigree with NEFL E396K mutation associated with a novel dominant intermediate Charcot-Marie-Tooth disease (DI-CMT) phenotype. The pedigree comprised four patients over two generations, aged between 35 and 59 years, wh o have been serially evaluated since 1993. Their clinical picture was characterized by pes cavus, sensorimotor neuropathy and spastic gait. Both older patients showed ascending leg weakness to involve pelvic musculature. CMT neuropathy score ranged from 14 to 26 (moderate to severe disease). Electrophysiology showed uniform nerve conduction slowing in the intermediate range, both in distal and proximal nerve segments. Multimodal evoked potential and blink reflex studies revealed abnormalities indicative of central sensorimotor pathway dysfunction. On imaging studies of lower-limb musculature, there was massive atrophy of intrinsic foot muscles and to a lesser degree of calves and thighs predominating in muscles innervated by tibial and sciatic nerves. In both patients exhibiting waddling gait, there was atrophy of pelvic muscles mainly involving gluteus medius, gluteus minimus and piriformis. We conclude that NEFL E396K mutation may manifest with a novel DI-CMT phenotype, characterized by simultaneous involvement of the peripheral and central nervous system. | 25877835 | 2015-04-01 |
| 11055725 | Targeting miR-381-NEFL axis sensitizes glioblastoma cells to temozolomide by regulating stemness factors and multidrug resistance factors. | Wang Z, etal., Oncotarget. 2015 Feb 20;6(5):3147-64. | MicroRNA-381 (miR-381) is a highly expressed onco-miRNA that is involved in malignant progression and has been suggested to be a good target for glioblastoma multiforme (GBM) therapy. In this study, we employed two-dimensional fluorescence differential gel electrophoresis (2-D DIGE) and MALDI-TOF/TO F-MS/MS to identify 27 differentially expressed proteins, including the significantly upregulated neurofilament light polypeptide (NEFL), in glioblastoma cells in which miR-381 expression was inhibited. We identified NEFL as a novel target molecule of miR-381 and a tumor suppressor gene. In human astrocytoma clinical specimens, NEFL was downregulated with increased levels of miR-381 expression. Either suppressing miR-381 or enforcing NEFL expression dramatically sensitized glioblastoma cells to temozolomide (TMZ), a promising chemotherapeutic agent for treating GBMs. The mechanism by which these cells were sensitized to TMZ was investigated by inhibiting various multidrug resistance factors (ABCG2, ABCC3, and ABCC5) and stemness factors (ALDH1, CD44, CKIT, KLF4, Nanog, Nestin, and SOX2). Our results further demonstrated that miR-381 overexpression reversed the viability of U251 cells exhibiting NEFL-mediated TMZ sensitivity. In addition, NEFL-siRNA also reversed the proliferation rate of U251 cells exhibiting locked nucleic acid (LNA)-anti-miR-381-mediated TMZ sensitivity. Overall, the miR-381-NEFL axis is important for TMZ resistance in GBM and may potentially serve as a novel therapeutic target for glioma. | 25605243 | 2015-04-01 |
| 1358514 | The novel neurofilament light (NEFL) mutation Glu397Lys is associated with a clinically and morphologically heterogeneous type of Charcot-Marie-Tooth neuropathy. | Zuchner S, etal., Neuromuscul Disord 2004 Feb;14(2):147-57. | Charcot-Marie-Tooth disease comprises a heterogeneous group of hereditary neuropathies which fall into two main groups: demyelinating CMT1 with reduced nerve conduction velocity and axonal CMT2 with normal nerve conduction velocity. The neuropathological features correspond in most cases to this cla ssification. Four genes were recently identified to cause autosomal dominant CMT2, including the neurofilament light gene. Thus far, only few mutations have been reported in neurofilament light involving eight amino acids of the gene. We identified a novel mutation, Glu397Lys, in a conserved motive signaling the end of the rod domain. The affected family members from three generations showed strikingly different clinical phenotypes, including weakness of the lower extremities, foot deformities, and deafness. The mutation was associated with nerve conduction velocities ranging from 27 m/s in a 25-year-old female to 43 m/s in an 82-year-old male in the lower extremity motor nerves. Sural nerve biopsies of two affected subjects were analyzed by light and electron microscopy. The pathological changes consisted of a reduction of predominantly large myelinated nerve fibers and various stages of onion bulb formation as typically seen in CMT1. This correlative study further confirms that neurofilament light gene mutations cause a wide clinical spectrum. Thus, analysis of the neurofilament light gene should not be restricted to pure axonal neuropathies. | 14733962 | 2004-06-01 |
