Pseudocatalytic Antiaggregation Activity of Antibodies: Immunoglobulins can Influence α-Synuclein Aggregation at Substoichiometric Concentrations

Abstract

Protein aggregation is involved in a variety of diseases. Alteration of the aggregation pathway, either to produce less toxic structures or to increase aggregate clearance, is a promising therapeutic route. Both active and passive immunization has been used for this purpose. However, the mechanism of action of antibodies on protein aggregates is not completely clear especially given poor ability of antibodies to cross blood-brain barrier. Here, we have shown that antibodies can interfere with protein aggregation at substoichiometric concentrations (as low as 1:1000 antibody to protein ratio). This is an indication that antibodies interact with aggregation intermediates in chaperone-like manner altering the aggregation pathways at very low antibody levels. This observation supports earlier suggestions that antibodies can inhibit aggregation by interaction with low abundance aggregation intermediates.

Autoimmune antibody decline in Parkinson’s disease and Multiple System Atrophy; a step towards immunotherapeutic strategies

“…Recent observations by Breydo et al have shown that antibodies can interfere with protein aggregation at substoichiometric concentrations [54]. Interestingly, Inhibition was especially effective in the absence of seeds indicating that early stages in the aggregation pathway were the major targets of the antibody binding.…”

Bacterial Chaperones CsgE and CsgC Differentially Modulate Human α-Synuclein Amyloid Formation via Transient Contacts

“…In analogy to our CsgC results, non-canonical ( i . e ., transient) interactions with α-synuclein monomers have been reported for DnaK that resulted in amyloid inhibition [ 38 ] and the anti-aggregation activity by antibodies on α-synuclein was reported to take place via a pseudo-catalytic mechanism [ 39 ]. In similarity to the CsgE results, FKBP12 was suggested to enhance α-synuclein aggregation via a catalytic mechanism involving transient interactions [ 40 ].…”

Mechanistic study of the inhibitory activity of Geum urbanum extract against α-Synuclein fibrillation

“…The conversion of unfolded monomeric -Synuclein into the fibrillar state occurs through a complex process involving formation of a premolten globule-like partially folded intermediate followed by the formation of an amyloidogenic nucleus and subsequent oligomerization and formation of protofibrils and fibrils. A common characteristic of these intermediates is the presence of substantial nonpolar patches which cause increased hydrophobic interaction between the molecules, resulting in aggregation [2][3][4][5][6][7][8][9][10]. Since protein aggregates can be observed before the onset of disease symptoms in neurodegenerative diseases, protein aggregation is a relevant target in the development of treatments and diagnostic tools.…”