Aggregation and Cellular Toxicity of Pathogenic or Non-pathogenic Proteins

Abstract

More than 20 unique diseases such as diabetes, Alzheimer’s disease, Parkinson’s disease are caused by the abnormal aggregations of pathogenic proteins such as amylin, β-amyloid (Aβ), and α-synuclein. All pathogenic proteins differ from each other in biological function, primary sequences, and morphologies; however, the proteins are toxic when aggregated. Here, we investigated the cellular toxicity of pathogenic or non-pathogenic protein aggregates. In this study, six proteins were selected and they were incubated at acid pH and high temperature. The aggregation kinetic and cellular toxicity of protein species with time were characterized. Three non-pathogenic proteins, bovine serum albumin (BSA), catalase, and pepsin at pH 2 and 65 °C were stable in protein structure and non-toxic at a lower concentration of 1 mg/mL. They formed aggregates at a higher concentration of 20 mg/mL with time and they induced the toxicity in short incubation time points, 10 min and 20 min only and they became non-toxic after 30 min. Other three pathogenic proteins, lysozyme, superoxide dismutase (SOD), and insulin, also produced the aggregates with time and they caused cytotoxicity at both 1 mg/mL and 20 mg/mL after 10 min. TEM images and DSC analysis demonstrated that fibrils or aggregates at 1 mg/mL induced cellular toxicity due to low thermal stability. In DSC data, fibrils or aggregates of pathogenic proteins had low thermal transition compared to fresh samples. The results provide useful information to understand the aggregation and cellular toxicity of pathogenic and non-pathogenic proteins.

PD-L1 Influences Cell Spreading, Migration and Invasion in Head and Neck Cancer Cells

“…In contrast, the overexpression of PD-L1 in PCI 52 with an abundant intrinsic PD-L1 expression led to a decrease in cell spreading on collagen type I and Matrigel ® . This might be due to the overload of PD-L1 expression (intrinsic plus overexpression), where cells have to prevent the aggregation of excessive proteins, which is toxic for cells at a certain concentration [44]. On the other hand, the siRNA knockdown of PD-L1 led to the decreased spreading of all HNSCC spheroids independent of surface coatings.…”

Zinc induced structural changes in the intrinsically disordered BDNF Met prodomain confer synaptic elimination

“…28,57 In contrast, misfolded, oligomeric pathogenic and nonpathogenic proteins or even small organic molecules forming colloidal aggregates can provoke interactions that often prove cytotoxic. [58][59][60][61] Promiscuous interactions in the extracellular spaces could potentially disrupt synaptic signaling and channel proteins. The most likely prodomain interaction in this context is SorCS2, that exists as a dimer, as assessed by X-ray crystallography and negatively stained electron microscopy.…”

Evidence of Anti-amyloid Characteristics of Plumbagin via Inhibition of Protein Aggregation and Disassembly of Protein Fibrils

“…8,15 Bovine serum albumin (BSA) is considered as one of the model amyloidogenic proteins for studying amyloid aggregation under in vitro conditions, 16,17 which has provided important information on the structural, biophysical, and cytotoxic properties of amyloid formation in non-pathogenic proteins. [7][8][9]18 Studies have revealed that the level of serum albumin is inversely linked with Aβ deposition and Aβ positivity. 19 Research reports have also shown that Aβ [25][26][27][28][29][30][31][32][33][34][35] can induce in vitro cross-seeding of BSA, resulting in aggregates that were toxic to microglial cells.…”