PABPC1 mediates degradation of C9orf72-FTLD/ALS GGGGCC repeat RNA

Uozumi R., Mori K., Gotoh S., et al. PABPC1 mediates degradation of C9orf72-FTLD/ALS GGGGCC repeat RNA. iScience 27, 109303 (2024); https://doi.org/10.1016/j.isci.2024.109303.GGGGCC hexanucleotide repeat expansion in C9orf72 causes frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Expanded GGGGCC repeat RNA accumulates within RNA foci and is translated into toxic dipeptide repeat proteins; thus, efficient repeat RNA degradation may alleviate diseases. hnRNPA3, one of the repeat RNA-binding proteins, has been implicated in the destabilization of repeat RNA. Using APEX2-mediated proximity biotinylation, here, we demonstrate PABPC1, a cytoplasmic poly (A)-binding protein, interacts with hnRNPA3. Knockdown of PABPC1 increased the accumulation of repeat RNA and RNA foci to the same extent as the knockdown of hnRNPA3. Proximity ligation assays indicated PABPC1-hnRNPA3 and PABPC1-RNA exosomes, a complex that degrades repeat RNA, preferentially co-localized when repeat RNA was present. Our results suggest that PABPC1 functions as a mediator of polyadenylated GGGGCC repeat RNA degradation through interactions with hnRNPA3 and RNA exosome complex

eIF5 stimulates the CUG initiation of RAN translation of poly-GA dipeptide repeat protein (DPR) in C9orf72 FTLD/ALS

Gotoh S., Mori K., Fujino Y., et al. eIF5 stimulates the CUG initiation of RAN translation of poly-GA dipeptide repeat protein (DPR) in C9orf72 FTLD/ALS. Journal of Biological Chemistry 300, 105703 (2024); https://doi.org/10.1016/j.jbc.2024.105703.Tandem GGGGCC repeat expansion in C9orf72 is a genetic cause of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Transcribed repeats are translated into dipeptide repeat proteins via repeat-associated non-AUG (RAN) translation. However, the regulatory mechanism of RAN translation remains unclear. Here, we reveal a GTPase-activating protein, eukaryotic initiation factor 5 (eIF5), which allosterically facilitates the conversion of eIF2-bound GTP into GDP upon start codon recognition, as a novel modifier of C9orf72 RAN translation. Compared to global translation, eIF5, but not its inactive mutants, preferentially stimulates poly-GA RAN translation. RAN translation is increased during integrated stress response, but the stimulatory effect of eIF5 on poly-GA RAN translation was additive to the increase of RAN translation during integrated stress response, with no further increase in phosphorylated eIF2α. Moreover, an alteration of the CUG near cognate codon to CCG or AUG in the poly-GA reading frame abolished the stimulatory effects, indicating that eIF5 primarily acts through the CUG-dependent initiation. Lastly, in a Drosophila model of C9orf72 FTLD/ALS that expresses GGGGCC repeats in the eye, knockdown of endogenous eIF5 by two independent RNAi strains significantly reduced poly-GA expressions, confirming in vivo effect of eIF5 on poly-GA RAN translation. Together, eIF5 stimulates the CUG initiation of poly-GA RAN translation in cellular and Drosophila disease models of C9orf72 FTLD/ALS

Significance of Impairment of Antioxidants in Colonic Epithelial Cells Isolated From TNBS-Iuduced Colitis Rats

The functional status of glutathione (GSH), its related enzymes and Cu, Zn-superoxide dismutase (SOD) in colonocytes isolated from trinitrobenzene sulphonic (TNBS)-induced colitis rats was studied. Colitis (T group) was induced in Wistar rats with 42 mg TNBS dissolved in 0.35 ml of 40% (v/v) ethanol instilled into the colon. The animals were sacrificed on day 14 and compared with saline-instilled rats (S group). The GSH concentration and the enzymatic activities of glutathione peroxidase (GPx), glutathione S-transferase (GST), and SOD were spectrophotometrically estimated. The severity of colitis was assessed histologically and by myeloperoxidase activity (MPO) in whole colonic tissue. The body weight loss of the rats in the T group was marked. In colonocytes isolated from rats in the T group, the concentration of GSH (7.9 ±1.4 vs.11.3 ± 0.4 nmol/mg protein, p < 0.05) and the activities of GST (104.4 ± 10.3 vs. 146.2 ± 18.5 mU/mg protein, p < 0.05) and SOD (74.4 ± 8.9 vs. 99.8 ± 7.5U/mg protein, p < 0.05) were lower, but the activity of GPx (430.0 -±14.1 vs. 283.9 ± 10.0 mU/mg protein, p < 0.05) was higher than in the S group. As expected, the activity of MPO in the T group was higher than in the S group (371.2 ± 14.7 vs. 158.9 ± 8.4 mU/mg tissue, p<0.05) and histologically, colitis was only observed in rats in the T group. In conclusion, the functional status of antioxidants in the colonic epithelial cells of rats challenged with TNBS solution is impaired. This impariment may make them more susceptible to oxidative damage that may contribute to the development of the lesions observed in this model. Further studies at the molecular level are necessary to investigate these novel findings in this model and their potential application for testing new therapeutic approaches in inflammatory diseases of the intestinal tract

Synergistic association of elevated serum free fatty acid and glucose levels with large arterial stiffness in a general population: The Nagahama Study.

[Background]Previous studies have reported that artificial increases in circulating free fatty acid (FFA) levels might have adverse effects on the vasculature. However, whether or not this effect can be extrapolated to physiological variations in FFA levels has not been clarified. Given that FFAs exert a lipotoxic effect on pancreatic β-cells and might directly damage the arterial endothelium, we hypothesized that these adverse effects might synergize with hyperglycemia. [Methods] A total of 9396 Japanese subjects were included in the study. Serum FFA levels were measured at baseline examination. Brachial-to-ankle pulse wave velocity (baPWV) was measured as an index of arterial stiffness. [Results] As serum levels of FFA were markedly lower in subjects with higher insulin level, a significant association between FFA levels and baPWV was observed only in subjects with blood samples taken under fasting (≥ 12 h, P < 0.001) or near-fasting (5–11 h, P < 0.001) conditions, and not in those taken under non-fasting (< 5 h, P = 0.307) conditions. Although type 2 diabetes and HbA1c showed a strong association with baPWV, the association between FFA level and baPWV remained significant (β = 0.052, P < 0.001) after adjustment for glycemic levels. In addition to their direct relationship, FFA and glucose levels were synergistically associated with baPWV (FFA⁎glucose; β = 0.036, P < 0.001). Differences in baPWV between the lowest and highest subgroups divided by a combination of FFA and glucose reached approximately 300 cm/s. [Conclusions] Physiological variations in FFA concentrations might be a risk factor for large arterial stiffness. FFA and hyperglycemia exert a synergistic adverse effect on the vasculature

Gait and posture assessments of a patient treated with deep brain stimulation in dystonia using three-dimensional motion analysis systems

Kinesiologic analysis of gait disorders, postural instabilities and abnormal movements is quite difficult to assess objectively by clinical observation, such as by specific scale and video recordings. In this study, we reported one of the aspects of the usefulness of three-dimensional motion analysis (Vicon Systems, Oxford, United Kingdom), which can measure inclusive data of movement disorders and substitute for conventional assessments. A 49-year-old man who had various dystonic symptoms, mainly on his left side of the body, responded well to deep brain stimulation (DBS). The examination quantified how the involuntary movements or other symptoms with dystonia changed before and after treatments

The Development of a Dual-Radar System with Automatic Hypopnea Threshold Optimization for Contact-Free Sleep Apnea-Hypopnea Syndrome Screening

Full-night polysomnography (PSG) examination is regarded as the gold standard for the diagnosis of sleep apnea-hypopnea syndrome (SAHS). However, PSG requires the placement of multiple sensors on the head, face, and chest, which can impose a heavy strain on patients. Therefore, in the present study, we aimed to develop a contact-free, stand-alone SAHS screening system that eliminates body movement artifacts based on automatic optimization of the hypopnea threshold. Doppler radar sensors were placed beneath a mattress. In order to achieve high sensitivity and specificity, the hypopnea was based on the average amplitude of respiration during the full sleep period. The threshold was determined via receiver operating characteristic (ROC) analysis using PSG as a reference. We conducted full-night clinical tests of the proposed system in 27 patients with suspected SAHS (49 ± 12 years) at Tomei Atsugi Hospital. When predicting the severity of SAHS with an apnea-hypopnea index (AHI) of >30/h using PSG as a reference, the proposed system achieved a sensitivity of 100% and a specificity of 100%. These results represent a drastic improvement over those of our previous study (sensitivity: 90%; specificity: 79%)