Effects of percutaneous endovascular angioplasty for severe stenosis or occlusion of subclavian artery.

To investigate the effect and safety of percutaneous endovascular angioplasty (PEA) with optional stenting for the treatment of severe stenosis or occlusion of subclavian artery, patients with severe stenosis ≥ 70% or occlusion of subclavian artery treated with PEA were retrospectively enrolled. The clinical data were analyzed. A total of 222 patients were retrospectively enrolled, including 151 males (68.0%) and 71 females (32.0%) aged 48-86 (mean 63.9 ± 9.0) years. Forty-seven (21.2%) patients had comorbidities. Subclavian artery stenosis ≥ 70% was present in 201 (90.5%) patients and complete subclavian occlusion in 21 (9.5%) cases. Angioplasty was successfully performed in all (100%) patients. Balloon-expandable stents were used in 190 (85.6%) cases, and self-expandable stents in 20 (9.0%) cases. Only 12 (5.4%) cases were treated with balloon dilation only. Among 210 patients treated with stent angioplasty, 71 (33.8% or 71/210) cases underwent balloon pre-dilation, 139 (66.2% or 139/210) had direct deployment of balloon-expandable stents, and 2 (1.0% or 2/210) experienced balloon post-dilation. Distal embolization protection devices were used in 5 (2.3% or 5/222) cases. Periprocedural complications occurred in 3 (1.4%) patients, including aortic dissection in 2 (0.9%) cases and right middle cerebral artery embolism in 1 (0.5%). No hemorrhage occurred. Among 182 (82.0%) patients with 6-month follow-up, restenosis > 70% occurred in 1 (0.5%) patient, and among 68 (30.6%) patients with 12-month follow-up, restenosis > 70% took place in 11 (16.2%) patients. Percutaneous endovascular angioplasty can be safely and efficiently performed for the treatment of severe stenosis ≥ 70% or occlusion of subclavian artery.

Tracking tumor evolution during the first-line treatment in brain glioma via serial profiling of cell-free tumor DNA from tumor in situ fluid.

Objective: Tumor in situ fluid (TISF) refers to the fluid within surgical cavities of glioma. Several studies preliminarily proved the value of cell-free tumor DNA (cf-tDNA) from TISF in the dynamic characterization of the glioma genome. Here, we assessed the potential utility of TISF cf-tDNA in broad aspects of tumor evolution under therapeutic pressure. Methods: This study was conducted under an Institutional Review Board-approved protocol at Henan Provincial People's Hospital (China). Cf-tDNA samples were sequenced with a designed 68-gene panel. A total of 205 cf-tDNA samples from 107 patients were studied. The clinical relevance of serial cf-tDNA profiling during the postoperative course was analyzed. Results: At least one tumor mutations were detected in 179/205 (87.3%) TISF cf-tDNA samples. Serial cf-tDNA was complementary to molecular residual disease and to initial tumors. Serial cf-tDNA revealed the selection of pre-existing mismatch repair-deficient cells by temozolomide as a resistant mechanism. Cf-tDNA parameters during treatment were predictive of recurrence, and serial cf-tDNA monitoring had diagnostic value for early recurrence. A total of 223 potentially actionable genomic alterations were assessed in cf-tDNA samples, wherein 78% were not found in any tumor tissue. Conclusions: In conclusion, serial TISF cf-tDNA profiling is valuable in tracking the tumor evolution of glioma during treatment and may be a feasible non-invasive option for monitoring glioma in future prospective studies and clinical practice.

Prognostic significance of white blood cell to platelet ratio in delayed cerebral ischemia and long-term clinical outcome after aneurysmal subarachnoid hemorrhage.

Objectives: The ratio of white blood cell to platelet count (WPR) is considered a promising biomarker in some diseases. However, its prediction of delayed cerebral ischemia (DCI) and prognosis after aneurysmal subarachnoid hemorrhage (aSAH) has not been studied. The primary objective of this study was to investigate the predictive value of WPR in DCI after aSAH and its impact on 90-day functional outcome. Materials and methods: This study retrospectively analyzed the data of blood biochemical parameters in 447 patients with aSAH at early admission. Univariate and multivariate analyses were used to determine the risk factors for DCI. According to multivariate analysis results, a nomogram for predicting DCI is developed and verified by R software. The influence of WPR on 90-day modified Rankin score (mRS) was also analyzed. Results: Among 447 patients with aSAH, 117 (26.17%) developed DCI during hospitalization. Multivariate logistic regression analysis showed that WPR [OR = 1.236; 95%CI: 1.058-1.444; p = 0.007] was an independent risk factor for DCI. The receiver operating characteristic (ROC) curve analysis was used to evaluate the predictive ability of WPR for DCI, and the cut-off value of 5.26 (AUC 0.804, 95% CI: 0.757-0.851, p < 0.001). The ROC curve (AUC 0.875, 95% CI: 0.836-0.913, p < 0.001) and calibration curve (mean absolute error = 0.017) showed that the nomogram had a good predictive ability for the occurrence of DCI. Finally, we also found that high WPR levels at admission were closely associated with poor prognosis. Conclusion: WPR level at admission is a novel serum marker for DCI and the poor prognosis after aSAH. A nomogram model containing early WPR will be of great value in predicting DCI after aSAH.

A correlation and prediction study of the poor prognosis of high-grade aneurysmal subarachnoid hemorrhage from the neutrophil percentage to albumin ratio.

OBJECTIVE: Inflammatory response and nutritional status play crucial roles in patients with aneurysmal subarachnoid hemorrhage (aSAH). This study mainly investigated the correlation between neutrophil percentage to albumin ratio (NPAR) and clinical prognosis in aSAH patients with high-grade Hunt-Hess and its predictive model. METHODS: A retrospective analysis was conducted based on 806 patients with aneurysmal subarachnoid hemorrhage who were admitted to the studied hospital from January 2017 to December 2021. Modified Fisher grade and Hunt-Hess grade were obtained according to their status at admission and hematological parameters within 48 h after hemorrhage. Univariate and multivariate logistic regression analysis were conducted to evaluate the relationship between NPAR and the clinical prognosis of patients with aSAH. And propensity matching analysis of patients with aSAH in the severe group. Receiver operating characteristic (ROC) curve analysis was used to determine the optimal cut-off value of NPAR at admission to predict prognosis and its sensitivity and specificity. The nomogram diagram and Calibration curve were further used to examine the prediction model. RESULTS: According to the mRS score at discharge, 184 (22.83 %) cases were classified as having poor outcomes (mRS > 2). Through multivariate logistic regression analysis, it was found that the Modified Fisher grade at admission, Hunt-Hess grade, eosinophils, neutrophil to lymphocyte ratio (NLR), and NPAR were independent risk factors for poor outcome in patients with aSAH (p < 0.05). The NPAR of aSAH patients with poor outcomes in the high-grade group was significantly higher than that in the low-grade group. The optimal cut-off value for NPAR was 21.90, the area under the ROC curve was 0.780 (95 % CI 0.700 - 0.861, p < 0.001). The Calibration curves show that the predicted probability of the drawn nomogram is overall consistent with the actual probability. (Mean absolute error = 0.031) CONCLUSION: The NPAR value of patients with aSAH at admission is significantly correlated with Hunt-Hess grade in a positive manner, namely, the higher the Hunt-Hess grade, the higher the NPAR value, and the worse the prognosis. Findings indicate that early NPAR value can be used as a feasible biomarker to predict the clinical prognosis of patients with aSAH.

Comprehensive analysis of autophagy-related gene expression profiles identified five gene biomarkers associated with immune infiltration and advanced plaques in carotid atherosclerosis.

BACKGROUND: Autophagy plays an important role in the progression of carotid atherosclerosis (CAS). This study aimed to identify hub autophagy-related genes (ATGs) associated with CAS. METHODS: GSE43292 and GSE28829 datasets of early and advanced CAS plaques were enrolled from the Gene Expression Omnibus (GEO) database. A comprehensive analysis of differentially expressed ATGs (DE-ATGs) was conducted. Functional enrichment assay was used to explore biological functions of DE-ATGs. The hub ATGs were identified by protein-protein interaction (PPI) network. Immunohistochemistry (IHC) and Real-time reverse transcription-quantitative polymerase chain reaction (RT-qPCR) were used to validate hub ATGs at the protein level and mRNA level. Correlation analysis of hub ATGs with immune cells was also conducted. In addition, a competitive endogenous RNA (ceRNA) network was constructed, and diagnostic value of hub ATGs was evaluated. RESULTS: A total of 19 DE-ATGs were identified in early and advanced CAS plaques. Functional enrichment analysis of DE-ATGs suggested that they were closely correlated to autophagy, apoptosis, and lipid regulation. Moreover, 5 hub ATGs, including TNFSF10, ITGA6, CTSD, CCL2, and CASP1, were identified and further verified by IHC. The area under the curve (AUC) values of the 5 hub ATGs were 0.818, 0.732, 0.792, 0.814, and 0.812, respectively. Competing endogenous RNA (ceRNA) networks targeting the hub ATGs were also constructed. In addition, the 5 hub ATGs were found to be closely associated with immune cell infiltration in CAS. CONCLUSION: In this study, we identified 5 hub ATGs including CASP1, CCL2, CTSD, ITGA6 and TNFSF10, which could serve as candidate diagnostic biomarkers and therapeutic targets.

Corrigendum: Clinical value and prognosis of C reactive protein to lymphocyte ratio in severe aneurysmal subarachnoid hemorrhage.

[This corrects the article DOI: 10.3389/fneur.2022.868764.].

Risk factors and predictive models of poor prognosis and delayed cerebral ischemia in aneurysmal subarachnoid hemorrhage complicated with hydrocephalus.

Objective: To evaluate the correlation of serum biological markers and related scales to the occurrence of delayed cerebral ischemia and clinical prognosis in patients with aneurysmal subarachnoid hemorrhage (aSAH) complicated with acute hydrocephalus before admission. Methods: The clinical data of 227 patients with pre-admission aSAH complicated with acute hydrocephalus admitted to Henan Provincial People's Hospital from April 2017 to December 2020 were retrospectively analyzed. Patients were grouped according to the presence or absence of delayed cerebral ischemia (DCI) after surgery and the prognosis at 6 months after discharge. Univariate and multivariable logistic regression analysis were performed to analyze the relationship between serum biological indicators combined with aneurysm related clinical score scale and the occurrence and prognosis of delayed cerebral ischemia. ROC curves and nomogram were drawn. Results: Multivariable Logistic regression analysis showed that high Hunt-Hess grade and surgical clipping were independent risk factors for postoperative DCI (P < 0.05). Older age, higher Hunt-Hess grade, higher CRP and neutrophil levels were independent risk factors for poor prognosis at 6 months after surgery (P < 0.05). ROC curve analysis showed that the area under the curve (AUC) of Hunt-Hess grade and surgical method for predicting DCI in patients with aSAH combined with hydrocephalus after surgery were 0.665 and 0.593. The combined AUC of Hunt-Hess grade and surgical method was 0.685, the sensitivity was 64.9%, and the specificity was 64.7%. The AUC of CRP, neutrophil, age and Hunt-Hess grade for predicting poor prognosis in patients with aSAH combined with hydrocephalus at 6 months after surgery were 0.804, 0.735, 0.596, 0.757, respectively. The combined AUC of CRP, neutrophil, age, Hunt-Hess grade was 0.879, the sensitivity was 79%, and the specificity was 84.5%. According to the correction curve, the predicted probability of the nomogram is basically consistent with the actual probability. Conclusion: Hunt-Hess grade and surgical method are independent predictors of postoperative DCI in patients with aSAH complicated with hydrocephalus. "CRP," "neutrophil," "age" and "Hunt-Hess grade" at admission are independent predictors of clinical prognosis in patients with aSAH complicated with hydrocephalus. The combination of the above indicators has high predictive value.

Clinical Value and Prognosis of C Reactive Protein to Lymphocyte Ratio in Severe Aneurysmal Subarachnoid Hemorrhage.

Objective: To investigate the relationship between CLR and disease severity and clinical prognosis of aSAH. Methods: The authors retrospectively analyzed the clinical data of 221 patients with aSAH, who were admitted to the intensive care unit from January 2017 to December 2020. The indicators of inflammatory factors in the first blood routine examination within 48 h of bleeding were obtained. The prognosis was evaluated by mRS score at discharge, mRS>2 was a poor outcome. Through the receiver operating characteristic (ROC) curve, the area under the curve was calculated and the predicted values of inflammatory factors (CLR, CRP, WBC, and neutrophils) were compared. Univariate and multivariable logistic regression analyses were used to evaluate the relationship between CLR and the clinical prognosis of patients. ROC curve analysis was performed to determine the optimal cut-off threshold, sensitivity, and specificity of CLR in predicting prognosis at admission. Results: According to the mRS score at discharge, 139 (62.90%) patients were classified with poor outcomes (mRS>2). The inflammatory factor with the best predictive value was CLR, which had an optimal cut-off threshold of 10.81 and an area under the ROC curve of 0.840 (95%CI.788-0.892, P < 0.001). Multivariable Logistic regression analysis showed that the Modified Fisher grade, Hunt-Hess grade, and CLR at admission were independent risk factors for poor outcomes of patients with aSAH (P < 0.05). According to Hunt-Hess grade, patients were divided into a mild group (Hunt-Hess ≤ 3) and a severe group (Hunt-Hess > 3), and the CLR value was significantly higher in severe patients with aSAH than in mild patients. The optimal cut-off threshold of CLR in the severe group was 6.87, and the area under the ROC curve was 0.838 (95% CI.752-0.925, P < 0.001). Conclusions: The CLR value at the admission of patients with aSAH was significantly associated with Hunt-Hess grade, The higher Hunt-Hess grade, the higher the CL R-value, and the worse the prognosis. Early CLR value can be considered as a feasible biomarker to predict the clinical prognosis of patients with aSAH.

Case Report: Internal Carotid Artery Thrombosis: A Rare Complication After Fibrin Glue Injection for Cavernous Sinus Hemostasis.

Background: Fibrin glue injection within the cavernous sinus (CS) is a demonstrably safe and simple technique to control venous bleeding with a low complication rate. However, this technique does have inherent risks. We illustrate 2 cases of internal carotid artery (ICA) thrombosis after fibrin glue injection in the CS for hemostasis. Methods: After encountering this complication recently, we conducted a retrospective review of the surgical database of 2 senior neurosurgeons who specialize in cerebrovascular and skull base surgery to identify patients with any complications associated with the use of fibrin glue injection for hemostasis. Approval was given by respective institutional review boards, and patient consent was obtained. Results: Of more than 10,000 microsurgery procedures performed by 2 senior neurosurgeons with a combined experience of 40 years, including procedures for aneurysms and skull base tumors, 2 cases were identified involving ICA thrombosis after fibrin glue injection in the CS for hemostasis. Both cases involved severe ischemic complications as a result of the ICA thrombosis. In this article, we present their clinical presentation, characteristics, management, and outcomes. Conclusion: Direct injection of fibrin glue into the CS for hemostasis can effectively control venous bleeding and facilitate complex dissections. However, it can be associated with ICA thrombosis, with subsequent serious ischemia and poor prognosis. Although this complication appears to be rare, increased awareness of this problem should temper the routine use of fibrin glue in anterior clinoidectomy and transcavernous approaches.

Tumor DNA From Tumor In Situ Fluid Reveals Mutation Landscape of Minimal Residual Disease After Glioma Surgery and Risk of Early Recurrence.

The recurrence of glioma is a difficult problem in clinical treatment. The molecular markers of primary tumors after resection cannot fully represent the characteristics of recurrent tumors. Here, abundant tumor DNA was detected in tumor in situ fluid (TISF). We report that TISF-derived tumor DNA (TISF-DNA) can detect genomic changes in recurrent tumors and facilitate recurrence risk analysis, providing valuable information for diagnosis and prognosis. The tumor DNA in TISF is more representative and sensitive than that in cerebrospinal fluid. It reveals the mutational landscape of minimal residual disease after glioma surgery and the risk of early recurrence, contributing to the clinical management and clinical research of glioma patients.

Constrained-Spherical Deconvolution Tractography in the Evaluation of the Corticospinal Tract in Glioma Surgery.

Introduction: Tractography has demonstrated utility for surgical resection in the setting of primary brain tumors involving eloquent white matter (WM) pathways. Methods: Twelve patients with glioma in or near eloquent motor areas were analyzed. The motor status was recorded before and after surgery. Two different tractography approaches were used to generate the motor corticospinal tract (CST): Constrained spherical deconvolution probabilistic tractography (CSD-Prob) and single tensor deterministic tractography (Tens-DET). To define the degree of disruption of the CST after surgical resection of the tumor, we calculated the percentage of the CST affected by surgical resection, which was then correlated with the postoperative motor status. Moreover, the fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) of the CST generated by the CSD-Prob and the Tens-DET was measured and compared between the ipsilesional and contralesional side. Results: The CST was identified in all patients and its trajectory was displaced by the tumor. Only the CSD-Prob approach showed the CST with the characteristic fan-like projections from the precentral gyrus to the brainstem. Disruption of the CST was identified in 6/6 with postoperative motor deficit by CSD-Prob approach and in 5/6 in the Tens-DET. The degree of disruption was significantly associated with the motor deficit with the CSD-Prob approach (rho = -0.88, p = 0.021). However, with the Tens-DET approach the CST disruption did not show significant association with the motor function (rho = -0.27, p = 0.6). There was a significant decrease in FA (p = 0.006) and a significant increase in MD (p = 0.0004) and RD (p = 0.005) on the ipsilesional CST compared with the contralesional CST only with the CSD-Prob approach. Conclusion: CSD-Prob accurately represented the known anatomy of the CST and provided a meaningful estimate of microstructural changes of the CST affected by the tumor and its macrostructural damage after surgery. Newer surgical planning stations should include advanced models and algorithms of tractography in order to obtain more meaningful reconstructions of the WM pathways during glioma surgery.

Characterizing the Genomic Landscape of Brain Glioma With Circulating Tumor DNA From Tumor In Situ Fluid.

Tumor in situ fluid (TISF) refers to the fluid at the local surgical cavity. We evaluated the feasibility of TISF-derived circulating tumor DNA (ctDNA) characterizing the genomic landscape for glioma. This retrospective study included TISF and tumor samples from 10 patients with glioma, we extracted cell-free DNA (cfDNA) from the TISF and then performed deep sequencing on that. And we compared genomic alterations between TISF and tumor tissue. Results showed that the concentration of cfDNA fragments from the patients for TISF ranged from 7.2 to 1,397 ng/ml. At least one tumor-specific mutation was identified in all 10 patients (100%). Further analysis of TISF ctDNA revealed a broad spectrum of genetic mutations, which have been reported to have clinical relevance. The analysis of concordance between TISF and tumor tissue reflected the spatiotemporal heterogeneity of glioma. Collectively, TISF ctDNA was a powerfully potential source for characterizing the genomic landscape of glioma, which provided new possibilities for precision medicine in patients with glioma.

Identification of PP2A and S6 Kinase as Modifiers of Leucine-Rich Repeat Kinase-Induced Neurotoxicity.

Mutations in LRRK2 are currently recognized as the most common monogenetic cause of Parkinsonism. The elevation of kinase activity of LRRK2 that frequently accompanies its mutations is widely thought to contribute to its toxicity. Accordingly, many groups have developed LRRK2-specific kinase inhibitors as a potential therapeutic strategy. Given that protein phosphorylation is a reversible event, we sought to elucidate the phosphatase(s) that can reverse LRRK2-mediated phosphorylation, with the view that targeting this phosphatase(s) may similarly be beneficial. Using an unbiased RNAi phosphatase screen conducted in a Drosophila LRRK2 model, we identified PP2A as a genetic modulator of LRRK2-induced neurotoxicity. Further, we also identified ribosomal S6 kinase (S6K), a target of PP2A, as a novel regulator of LRRK2 function. Finally, we showed that modulation of PP2A or S6K activities ameliorates LRRK2-associated disease phenotype in Drosophila.

A Pilot Study of Urinary Exosomes in Alzheimer's Disease.

BACKGROUND: Exosomes are nano-sized extracellular vesicles secreted by most cell types and abundantly present in body fluids, including blood, saliva, urine, cerebrospinal fluid, and breast milk. Exosomes can spread toxic amyloid-beta (Aß) and hyperphosphorylated tau between cells, contributing to neuronal loss in Alzheimer's disease (AD). OBJECTIVE: To explore changes in the morphology, number, and pathological protein levels of urinary exosomes in AD patients compared with age-matched healthy subjects. METHODS: In this study, enzyme-linked immunosorbent assay was used to detect the levels of Aß1-42 and P-S396-tau (normalized by CD63) in urinary exosomes of AD patients and matched healthy subjects. We used transmission electron microscopy and nanoparticle tracking analysis to observe the exosomes. RESULTS: We found that the levels of Aß1-42 and P-S396-tau in the urinary exosomes of AD patients were higher than those of matched healthy controls. Exosomes taken from AD patients were more numerous. CONCLUSION: The differences in levels of Aß1-42 and P-S396-tau and the quantity of urinary exosomes between AD patients and healthy controls may provide a basis for early diagnosis of AD.

A novel SETX gene mutation associated with Juvenile amyotrophic lateral sclerosis.

OBJECTS: This study aimed to report a novel point mutation associated with juvenile amyotrophic lateral sclerosis (JALS) in a Chinese Han family. METHODS: Detailed clinical assessment was applied to two patients, including proband (II-2) and his mother (I-2). Next-generation sequencing (NGS), also known as high-throughput sequencing in whole exon sequence, was performed in the proband to reach the target region. Sanger sequencing was also used to detect DNA sequence variants of the proband and other three members of his family. RESULTS: The proband (II-2) and his mother (I-2) were successfully diagnosed according to the clinical manifestations and physical examination. A novel point mutation c.1157T > C in the exon 10 of the SETX gene was identified in II-2 and I-2, resulting in a substitution of methionine (ATG) to threonine (ACG). However, we ultimately did not find the same variant in the other two normal members of his family in addition to 100 unrelated normal subjects. CONCLUSION: We presented a novel probably pathogenic missense mutation in exon 10 of SETX gene in a Chinese Han family with JALS.

A novel KIAA0196 mutation in a Chinese patient with spastic paraplegia 8: A case report.

RATIONALE: We report a case of Spastic paraplegia 8 (SPG8) with a novel mutation of KIAA0196 gene. PATIENTS CONCERNS: A 12-year-old boy presented as ankle sprained, lower limb stiffness, abnormal gait since he was 5 years old. DIAGNOSES: The next generation sequence showed a novel c.1128delG (p.L376fs) mutation in KIAA0196 gene, the electromyography showed the pyramidal tract conduction dysfunction and deep sensory conduction abnormalities of lower limbs without motor neuron damage. The diagnose was SPG8. INTERVENTIONS: Patient was gaven Baclofen treatment (30 mg/day, orally). OUTCOMES: At one year follow up, his symptoms didn't improved. LESSONS: We describe a novel KIAA0196 c.1128del.G (p.L376fs) mutation in a Chinese patient with SPG8. To our knowledge, it's the first frame delete mutation causing shift mutation of KIAA0196 gene, resulting in the earliest onset of SPG8 in the world. Gene sequencing is a powerful diagnostic tool to identify a causal mutation in genetically heterogeneous HSP.

LRRK2 interacts with ATM and regulates Mdm2-p53 cell proliferation axis in response to genotoxic stress.

Pathogenic leucine-rich repeat kinase 2 (LRRK2) mutations are recognized as the most common cause of familial Parkinson's disease in certain populations. Recently, LRRK2 mutations were shown to be associated with a higher risk of hormone-related cancers. However, how LRRK2 itself contributes to cancer risk remains unknown. DNA damage causes cancer, and DNA damage responses are among the most important pathways in cancer biology. To understand the role of LRRK2 in DNA damage response pathway, we induced DNA damage by applying genotoxic stress to the cells with Adriamycin. We found that DNA damage enhances LRRK2 phosphorylation at Serine 910, Serine 935 and Serine 1292. We further showed that LRRK2 phosphorylation is abolished in the absence of ATM, suggesting that LRRK2 phosphorylation requires ATM. It should also be noted that LRRK2 interacts with ATM. In contrast, overexpression or knockdown of LRRK2 does not affect ATM phosphorylation, indicating that LRRK2 is the downstream target of ATM in response to DNA damage. Moreover, we demonstrated that LRRK2 increases the expression of p53 and p21 by increasing the Mdm2 phosphorylation in response to DNA damage. Loss-of-function in LRRK2 has the opposite effect to that of LRRK2. In addition, FACS analysis revealed that LRRK2 enhances cell cycle progression into S phase in response to DNA damage, a finding that was confirmed by 5-bromo-2'-deoxyuridine immunostaining. Taken together, our findings demonstrate that LRRK2 plays an important role in the ATM-Mdm2-p53 pathway that regulates cell proliferation in response to DNA damage.

Phosphorylation of amyloid precursor protein by mutant LRRK2 promotes AICD activity and neurotoxicity in Parkinson's disease.

Mutations in LRRK2, which encodes leucine-rich repeat kinase 2, are the most common genetic cause of familial and sporadic Parkinson's disease (PD), a degenerative disease of the central nervous system that causes impaired motor function and, in advanced stages, dementia. Dementia is a common symptom of another neurodegenerative disease, Alzheimer's disease, and research suggests that there may be pathophysiological and genetic links between the two diseases. Aggregates of ß amyloid [a protein produced through cleavage of amyloid precursor protein (APP)] are seen in both diseases and in PD patients carrying G2019S-mutant LRRK2. Using patient-derived cells, brain tissue, and PD model mice, we found that LRRK2 interacted with and phosphorylated APP at Thr668 within its intracellular domain (AICD). Phosphorylation of APP at Thr668 promoted AICD transcriptional activity and correlated with increased nuclear abundance of AICD and decreased abundance of a dopaminergic neuron marker in cultures and brain tissue. The AICD regulates the transcription of genes involved in cytoskeletal dynamics and apoptosis. Overexpression of AICD, but not a phosphodeficient mutant (AICDT668A), increased the loss of dopaminergic neurons in older mice expressing LRRK2G2019S Moreover, the amount of Thr668-phosphorylated APP was substantially greater in postmortem brain tissue and dopaminergic neurons (generated by reprogramming skin cells) from LRRK2G2019S patients than in those from healthy individuals. LRRK2 inhibitors reduced the phosphorylation of APP at Thr668 in the patient-derived dopaminergic neurons and in the midbrains of LRRK2G2019S mice. Thus, APP is a substrate of LRRK2, and its phosphorylation promotes AICD function and neurotoxicity in PD.

MiRNA-128 regulates the proliferation and neurogenesis of neural precursors by targeting PCM1 in the developing cortex.

During the development, tight regulation of the expansion of neural progenitor cells (NPCs) and their differentiation into neurons is crucial for normal cortical formation and function. In this study, we demonstrate that microRNA (miR)-128 regulates the proliferation and differentiation of NPCs by repressing pericentriolar material 1 (PCM1). Specifically, overexpression of miR-128 reduced NPC proliferation but promoted NPC differentiation into neurons both in vivo and in vitro. In contrast, the reduction of endogenous miR-128 elicited the opposite effects. Overexpression of miR-128 suppressed the translation of PCM1, and knockdown of endogenous PCM1 phenocopied the observed effects of miR-128 overexpression. Furthermore, concomitant overexpression of PCM1 and miR-128 in NPCs rescued the phenotype associated with miR-128 overexpression, enhancing neurogenesis but inhibiting proliferation, both in vitro and in utero. Taken together, these results demonstrate a novel mechanism by which miR-128 regulates the proliferation and differentiation of NPCs in the developing neocortex.