C9orf72 Expansion Disrupts ATM-mediated Chromosomal Break Repair

A hexanucleotide repeat expansion represents the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia, though the mechanisms by which the expansion cause neurodegeneration are poorly understood. We report elevated levels of DNA/RNA hybrids (R-loops) and double-strand breaks (DSBs) in rodent neurons, human cells, and in C9orf72-ALS patient spinal cord tissues. Accumulation of endogenous DNA damage is concomitant with defective ATM-mediated DNA repair signalling and accumulation of protein-linked DNA breaks. We further reveal that defective ATM-mediated DNA repair is a consequence of p62 accumulation, which impairs H2A ubiquitylation and perturbs ATM signalling. Adeno-associated virus- mediated expression of C9orf72-related RNA and dipeptide repeats in the murine central nervous system causes elevated DSBs, ATM defects, and triggers neurodegeneration. These findings identify R-Loops, DSBs, and defective ATM-mediated repair as pathological consequences of C9orf72 expansions, and suggest that C9orf72-linked neurodegeneration is driven, at least in part, by genomic instability

Metabolic Implications of Hepatitis C Virus Infection and it's Correlation to Steatohepatitis in Chronic Hepatitis C Patients with and without Type 2 Diabetes

Background Chronic hepatitis C virus (HCV) infection is not a simple viral infection; it has many metabolic and autoimmune complications. Objective To investigate the impacts of chronic HCV infection on glucose and lipid metabolism and its correlation-if any-with body mass index (BMI) and hepatosteatosis in chronic HCV patients. Patients and Methods One hundred and three (103) chronic HCV patients were involved in this study. After blood sugar testing patients were classified into three groups; Group I: 68 chronic HCV patients with type 2 diabetes. Group II: 35 chronic HCV patients without Type 2 Diabetes and Group III: 25 patients with Type 2 Diabetes as a control group. With informed written consents and approval from Ain Shams medical ethics committee, all groups were subjected to the following: full history taking, thorough clinical examination, calculation of BMI, and measurement of the waist/hip ratio were done. Assessment of fasting plasma insulin level was done by the immune-enzymatic method. Assessment of the insulin resistance state was done by Homeostatic Model Assessment (HOMA-IR). Detection of anti-HCV was done by the 3rd generation ELISA test and confirmed by qualitative polymerase chain reaction (PCR). Results Diabetic and non diabetic chronic HCV patients were found to have significantly higher fasting plasma insulin levels and insulin resistance states than the control group. This insulin resistance was not due to increased body mass index as there was a non significant difference in BMI between all the studied groups. Positive correlations were found between plasma insulin level, liver enzymes and steatohepatitis in HCV patients whether they were diabetic or not. No correlation was found between BMI and plasma insulin level in group II patients (HCV only). Conclusion Chronic HCV infection may be regarded as an independent risk factor for the development of insulin resistance and type 2 diabetes. HCV induces insulin resistance; the key step for glucose intolerance, and virus C induced steatohepatitis therefore leading to faster progression to cirrhosis. The impacts of chronic HCV infection on glucose and lipid metabolism should be recognized in clinical care centers and addressed in future studies

Impact of circ-0000221 in the Pathogenesis of Hepatocellular via Modulation of miR-661–PTPN11 mRNA Axis

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death in Egypt. A deep understanding of the molecular events occurring in HCC can facilitate the development of novel diagnostic and/or therapeutic approaches. In the present study, we describe a novel axis of hsa-circ-0000221–miR-661–PTPN11 mRNA proposed by in silico and in vitro analysis and its role in HCC pathogenesis. We observe a reduction in the expression levels of hsa-circ-0000221 and PTPN11 mRNA in HCC patients’ sera tested compared with control subjects. The reduction occurs with a concomitant increase in the expression of miR-661. Furthermore, the introduction of exogenous hsa-circ-0000221 into Hep-G2 or SNU449 cell lines results in detectable decrease in cellular viability and an increase in apoptotic manifestations that is associated with G1 accumulation and CCDN1 overexpression. Altogether, these findings indicate the tumor-suppressive role of hsa-circ-0000221 in HCC, which acts through miR-661 inhibition, along with a subsequent PTPN11 mRNA increase, where PTPN11 is known to inhibit cell proliferation in many forms of cancer. Our study encourages further investigation of the role of circRNAs in cancer and their potential use as molecular biomarkers