Autoantibodies to α-synuclein protein and its amyloidogenic aggregates in humoral mechanisms of immunity in Parkinson's disease and experimental modeling

Abstract

A mismatch of the self-regulated operation of physiological systems with the external environment may lead to maladaptive disorders through persistently dysregulated cascades. We maintain that in the case of Parkinson's disease (PD), an immune-inflammatory-amyloid cascade develops, which changes the configuration of functional systems in the healthy body. The increasing incidence of neurodegenerative diseases, in particular PD, poses a challenge for developing new diagnostic technologies and methods for the targeted protection of brain cells from degeneration and death, (for example, by means of neuroimmunoprotective mechanisms). We have focused on disruption of the conformation of α-synuclein protein, a biomarker of PD, with the subsequent deposition of its protein aggregates in tissues, as one of the key reasons for the development of neurodegeneration in PD. The onset of PD neuropathology is based on complex processes, the main molecular mechanisms of which are: the formation of toxic amyloidogenic forms of α-synuclein, inflammation and autoimmune reactions to active brain factors, as well as endocrine disorders. It has been shown that intermediate forms of protein aggregates (oligomers) induce the death of both nerve and glial cells by apoptosis. In this regard, an area of topical investigation is the study of immunological protection of the brain from toxic oligomeric protein species. Thus, methods utilizing atomic force microscopy and labeling with specific dyes have been employed to characterize amyloidogenic proteins and their aggregates. In addition, the level of antibodies in the blood serum of patients with PD has been analyzed by ELISA. The dynamics of autoantibody production to morphologically characterized oligomeric fibrillar forms of α-synuclein, along with insulin as a marker of the endocrine system, neurotrophic factor S100b, and the neurotransmitter dopamine have all been examined. It has been disclosed that there are specific interrelationships between different conformational forms of these biomolecules, production of autoantibodies to them, and the development of neurodegeneration. Such findings raise the possibility of determining the role of the immune system in mechanisms of brain cell protection against damage and death during initial and progressive stages of PD neurodegeneration. It is also conceivable that this type of data will be beneficial in the development of targeted neuroimmunoprotection for the treatment of diseases associated with impaired protein folding.