Background: Intracerebral hemorrhage (ICH) is a stroke syndrome with an unfavorable prognosis. Currently, there is no comprehensive clinical indicator for mortality prediction of ICH patients. The purpose of our study was to construct and evaluate a nomogram for predicting the 30-day mortality risk of ICH patients.Methods: ICH patients were extracted from the MIMIC-III database according to the ICD-9 code and randomly divided into training and verification cohorts. The least absolute shrinkage and selection operator (LASSO) method and multivariate logistic regression were applied to determine independent risk factors. These risk factors were used to construct a nomogram model for predicting the 30-day mortality risk of ICH patients. The nomogram was verified by the area under the receiver operating characteristic curve (AUC), integrated discrimination improvement (IDI), net reclassification improvement (NRI), and decision curve analysis (DCA).Results: A total of 890 ICH patients were included in the study. Logistic regression analysis revealed that age (OR = 1.05, P < 0.001), Glasgow Coma Scale score (OR = 0.91, P < 0.001), creatinine (OR = 1.30, P < 0.001), white blood cell count (OR = 1.10, P < 0.001), temperature (OR = 1.73, P < 0.001), glucose (OR = 1.01, P < 0.001), urine output (OR = 1.00, P = 0.020), and bleeding volume (OR = 1.02, P < 0.001) were independent risk factors for 30-day mortality of ICH patients. The calibration curve indicated that the nomogram was well calibrated. When predicting the 30-day mortality risk, the nomogram exhibited good discrimination in the training and validation cohorts (C-index: 0.782 and 0.778, respectively). The AUCs were 0.778, 0.733, and 0.728 for the nomogram, Simplified Acute Physiology Score II (SAPSII), and Oxford Acute Severity of Illness Score (OASIS), respectively, in the validation cohort. The IDI and NRI calculations and DCA analysis revealed that the nomogram model had a greater net benefit than the SAPSII and OASIS scoring systems.Conclusion: This study identified independent risk factors for 30-day mortality of ICH patients and constructed a predictive nomogram model, which may help to improve the prognosis of ICH patients.

Spastin, a microtubule-severing enzyme, is important for neurite outgrowth. However, the mechanisms underlying the post-transcriptional regulation of spastin during microtubule-related processes are largely unknown. We demonstrated that the spastin expression level is controlled by a long non-coding RNA (lncRNA) metastasis-associated lung adenocarcinoma transcript 1 (MALAT1)/microRNA-30 (miR-30) axis during neurite outgrowth. The miR-30 expression level decreased in hippocampal neurons with increasing days in culture, and miR-30 overexpression suppressed while miR-30 inhibition promoted neurite outgrowth in hippocampal neurons. Spastin was validated as a target gene of miR-30 using the luciferase reporter assay. The protein expression, microtubule severing activity, and neurite promoting effect of spastin were suppressed by the overexpression of miR-30 mimics and increased by miR-30 inhibitors. MALAT1 expression increased during neurite outgrowth and MALAT1 silencing impaired neurite outgrowth. miR-30 was a sponge target of MALAT1 and MALAT1/miR-30 altered neurite outgrowth in hippocampal neurons. MALAT1 overexpression reversed the inhibitory effect of miR-30 on the activity of a luciferase reporter construct containing spastin, as well as spastin mRNA and protein expression, indicating that spastin was a downstream effector of MALAT1/miR-30. The MALAT1/miR-30 cascade also modulated spastin-induced microtubule severing, and the MALAT1/miR-30/spastin axis regulated neurite outgrowth in hippocampal neurons. This study suggests a new mechanism governing neurite outgrowth in hippocampal neurons involving MALAT1/miR-30-regulated spastin expression.

Dendritic spines are specialized structures involved in neuronal processes on which excitatory synaptic contact occurs. The microtubule cytoskeleton is vital for maintaining spine morphology and mature synapses. Spastin is related to microtubule-severing proteases and is involved in synaptic bouton formation. However, it is not yet known if spastin can be modified by Small Ubiquitin-like Modifier (SUMO) or how this modification regulates dendritic spines. Spastin was shown to be SUMOylated at K427, and its deSUMOylation promoted microtubule stability. In addition, SUMOylation of spastin was shown to affect signalling pathways associated with long term synaptic depression. SUMOylated spastin promoted the development of dendrites and dendritic spines. Moreover, SUMOylated spastin regulated endocytosis and affected the transport of the AMPA receptor, GluA1. Our findings suggest that SUMOylation of spastin promotes GluA1 internalization and regulates dendritic spine morphology through targeting of microtubule dynamics.

Amyloid-β(Aβ) plays an important role in Alzheimer’s disease (AD), as oligomeric Aβinduces loss of postsynaptic AMPA receptors (AMPARs) leading to cognitive deficits. The loss of postsynaptic AMPARs is mediated through the clathrin-dependent endocytosis pathway, in which endophilin2 is one of the important regulatory proteins. Endophilin2, which is enriched in both the pre- and postsynaptic membrane, has previously been reported to be important for recycling of synaptic vesicles at the presynaptic membrane. However, the role of endophilin2 in oligomeric Aβ-induced postsynaptic AMPAR endocytosis is not well understood. In this study, we show that endophilin2 does not affect constitutive AMPAR endocytosis. Endophilin2 knockdown, but not overexpression, resisted oligomeric Aβ-induced AMPAR dysfunction. Moreover, endophilin2 colocalized and interacted with GluA1, a subunit of AMPAR, to regulate oligomeric Aβ-induced AMPAR endocytosis. Thus, we have determined a role of endophilin2 in oligomeric Aβ-induced postsynaptic AMPAR dysfunction, indicating possible directions for preventing the loss of AMPARs in cognitive impairment and providing evidence for the clinical treatment of AD.

Plexin family proteins mediate semaphorin signalling during dendritic arbour development. However, the role of PlexinA3 in the growth of dendrites of cultured cerebellar granule neurons (CGNs) is not known. We found that PlexinA3 colocalizes with CRMP2 (collapsin response mediator protein 2) in dendritic shafts. Immunoprecipitation and glutathione transferase pulldown assays showed that the intracellular Ras-binding domain of PlexinA3 directly interacts with CRMP2. PlexinA3 was necessary and sufficient for the growth of CGN dendrites, as genetic knockdown of PlexinA3 reduced but its overexpression increased dendritic lengths and dendritic tip numbers. These increases were enhanced with CRMP2 overexpression and abolished with CRMP2 knockdown, indicating that CRMP2 is the downstream effector. Furthermore, PlexinA3/CRMP2 signalling contributed to Sema3A-controlled dendritic growth. Together, these data identify a novel PlexinA3/CRMP2 pathway in semaphorin-regulated growth of cultured CGN dendrites.

Hyperammonemia in the CNS induces irreversible damages to neurons due to ultimate cell loss. Neurite degeneration, a primary event that leads to neuronal cell death, remains less elucidated especially in hyperammonemia circumstances. Here, we found that the administration of ammonia induced neurite degeneration in cultured cerebellar granule neurons. The resulting altered neuronal morphology, rupture of neurites, and disassembly of the cytoskeleton led to cell death. Calcein and Fluo-4 staining revealed that ammonia induced intracellular calcium dysregulation. Subsequently activated calpain cleaved CRMP-2, a microtubule assembly protein. Pharmacologically inhibition of calpain, but not caspases or GSK-3, suppressed the cleavage of CRMP-2 and reversed neurite degeneration under ammonia treatment. Exposure to ammonia decreased whereas inhibition of calpain restored the amplitude and frequency of miniature excitatory postsynaptic currents. These data suggest a mechanism by which elevated ammonia level may induce neuronal dysfunction via abnormal calcium influx and calpain-dependent CRMP-2 cleavage, leading to abnormal synaptic transmission, cytoskeletal collapse, and neurite degeneration.