Complement modulation reverses pathology inY402H-retinal pigment epithelium cell model of age-related macular degeneration by restoring lysosomal function
STEM CELLS TRANSLATIONAL MEDICINE
Authors: Cerniauskas, Edvinas; Kurzawa-Akanbi, Marzena; Xie, Long; Hallam, Dean; Moya-Molina, Marina; White, Kathryn; Steer, David; Doherty, Mary; Whitfield, Phil; Al-Aama, Jumana; Armstrong, Lyle; Kavanagh, David; Lambris, John D.; Korolchuk, Viktor, I; Harris, Claire; Lako, Majlinda
Abstract
Age-related macular degeneration (AMD) is a multifactorial disease, which is characterized by loss of central vision, affecting one in three people by the age of 75. The Y402H polymorphism in the complement factor H (CFH) gene significantly increases the risk of AMD. We show that Y402H-AMD-patient-specific retinal pigment epithelium (RPE) cells are characterized by a significant reduction in the number of melanosomes, an increased number of swollen lysosome-like-vesicles with fragile membranes, Cathepsin D leakage into drusen-like deposits and reduced lysosomal function. The turnover of C3 is increased significantly in high-risk RPE cells, resulting in higher internalization and deposition of the Terminal Complement ComplexC5b-9at the lysosomes. Inhibition of C3 processing via the compstatin analogue Cp40 reverses the disease phenotypes by relieving the lysosomes of their overburden and restoring their function. These findings suggest that modulation of the complement system represents a useful therapeutic approach for AMD patients associated with complement dysregulation.
Mass spectrometry identification of potential biomarker proteins in the 150-kD electrophoretic band in patients with schizophrenia
MEDICINE
Authors: Xu, Ruihuan; Liang, Jingwen; Luo, Yi; Wan, Xing; Li, Kang; Qi, Liguo; Yuan, Wenbin; Chen, Jianxia; Wu, Ze; Wang, Mingbang; Zhou, Jiaxiu; Xie, Yingjun; Zhou, Shaoming; He, Fusheng
Abstract
Background: Diagnosing schizophrenia is primarily based on the presentation of defined signs and symptoms, none of which is pathognomonic for this group of syndromes. However, few significant genome-wide associations between schizophrenia and individual have detected. Protein profiling of candidate serum biomarkers in schizophrenia is therefore an area of great interest. Methods: In the present study, we used a combination of 7% polyethylene glycol (PEG) enrichment of immune complexes and sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) to separate abnormal band, then analyse the band with liquid chromatography mass spectrometry (LC-MS). Results: There is a special 150-kD electrophoretic band in patients with schizophrenia, bipolar disorder, or depression relative to healthy controls (each 30 samples). Analysis of the band using LC-MS resulted in the identification of 11 serum proteins whose abundance was altered between patients and controls. Among them, 8 proteins (CFH, CFB, cDNA FLJ75416, zinc finger protein 729, isoform 2 of nidogen-1, diaphanous-1, cDNA FLJ77762, and cDNA FLJ58411) were up regulated, while one protein (isoform 1 of collagen alpha-1 (II) was down regulated in patients with schizophrenia, but only zinc finger protein 729 has statistics significance (P <.05). No differences were noted with regard to thrombospondin-1 or collagen alpha-2 (I) among the 3 groups. These proteins take part in several biological functions such as focal adhesion, complement cascades, ECM-receptor interaction, and Staphylococcus aureus infection. Conclusions: The 150-kD electrophoretic band or zinc finger protein 729 may become biomarkers in patients with schizophrenia. In the future increasing sample size and function research of zinc finger protein 729 should be executed continuously.