Cross-linked amyloidogenic proteins as potential aggregation inhibitors

ABSTRACT: Amyloidogenic proteins, characterized by their ability to form fibrillar aggregates with β sheet structure play an important role in several degenerative diseases, including Parkinson’s disease. Numerous amyloidogenic proteins, such as α synuclein, are intrinsically disordered (or contain ID regions, hence they also present as highly dynamic conformational ensembles in these regions. Aggregation is an inherent property of the polypeptide chains and under non physiological, appropriate conditions most of the proteins can aggregate and form polymers of various structures. Since amyloid fib ril s and oligomers are associated with a great variety of human diseases, inhibition of protein aggregation has great importance and it can be addressed by using small molecules, peptides or proteins. Our research aim was to study the potential application of modified forms of different amyloidogenic proteins as inhibitor molecules by introducing structural constraints in them. Under various conditions, different amyloidogenic proteins’ (α-synuclein and β2-microglobulin) monomer molecules have been cross linked intramolecularly and the heterogeneous mixtures has been fractionated by HPLC. The inhibitory potential of the isolated and effective molecules has been experimentally investigated by various methods ThT assay, TEM, CD spectroscopy). Furthermore, the locations of the crosslinks in the molecules were determined by mass spectrometry, and their structures are modeled in silico. Our results revealed that conformational constrains applied by cross linking on amyloidogenic proteins block their amyloid formation. Moreover, these molecules exhibited inhibitory effect on the aggregation of the unmodified proteins, as well.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human) Escherichia Coli

DISEASE(S): Parkinson's Disease

SUBMITTER: Gabriella Gellen  

LAB HEAD: Dr. Gitta Schlosser

PROVIDER: PXD042501 | Pride | 2023-10-24

REPOSITORIES: Pride