The Role of Synucleins in Epileptogenesis

Synucleinopathies are a group of disorders associated with the abnormal aggregation of proteins from the synuclein family. Aggregated α-synuclein is a histopathological hallmark of Parkinson’s disease and several other synucleinopathies, such as dementia with Lewy bodies and multiple system atrophy.Under normal conditions, α-, β-, and γ-synucleins exist in a monomeric form and perform a number of physiological functions, including the regulation of synaptic transmission and intracellular transport. However, under the influence of various pathological factors, they can transition into an aggregated state, acquiring toxic properties and thereby contributing to the development of neuropathologies.Nevertheless, synuclein aggregation-related disorders are not limited to neurodegenerative diseases, as they affect organ systems throughout the body. Given that most of these diseases are incurable and, moreover, lack early diagnostic biomarkers, the study of synuclein functions remains a pressing area of neuroscience research.In this review, we critically examine the impact of pathological synuclein behavior on the body and their involvement in processes related to seizures and epilepsy.Over the past decades, growing evidence suggests that α-synuclein may also play a significant role in epileptogenesis. Pathological aggregation of this protein promotes the activation of neurotoxic mechanisms, including increased oxidative stress, initiation of neuroinflammation, and reduced efficiency of neurotransmitter release. Several experimental and clinical studies have shown that α-synuclein dysfunction may contribute to the emergence of seizure activity. Of particular interest are studies that have found elevated levels of α-synuclein in the blood serum and cerebrospinal fluid of patients with pharmacoresistant epilepsy, indicating not only its potential role in the pathogenesis of the disease but also its potential as a biomarker.Furthermore, there is a basis for investigating the roles of other members of the synuclein family—β- and γ-synucleins—though currently, there is significantly less data on them. Summarizing and systematizing the existing information on the possible connection between synucleins and epileptic processes could lead to a deeper understanding of the molecular mechanisms of epileptogenesis, and potentially uncover new therapeutic targets and methods for early diagnosis.