The role of synucleins in epileptogenesis

Synucleinopathies are a group of disorders associated with abnormal aggregation of synuclein family proteins. Aggregated alpha-synuclein serves as a histopathological hallmark of Parkinson disease and several other synucleinopathies, including dementia with Lewy bodies and multiple system atrophy. Under physiological conditions, alpha-, beta-, and gamma-synucleins exist in monomeric form and perform several functions, including regulation of synaptic transmission and intracellular transport. However, under the influence of various pathological factors, these proteins may undergo aggregation, acquire toxic properties, and thereby contribute to the development of neuropathological conditions. Nevertheless, synuclein aggregation–related disturbances are not confined to neurodegenerative disorders and may affect multiple organ systems. Considering that most of these diseases are currently incurable and lack reliable biomarkers for early diagnosis, investigation of synuclein function remains an important area of neuroscience research. In this review, we critically examine the impact of pathological synuclein behavior on the organism and their involvement in processes associated with seizures and epilepsy. In recent decades, accumulating evidence suggests that alpha-synuclein may play a substantial role in epileptogenesis. Pathological aggregation of this protein contributes to activation of neurotoxic mechanisms, including enhancement of oxidative stress, induction of neuroinflammation, and reduced efficiency of neurotransmitter release. Experimental and clinical studies indicate that alpha-synuclein dysfunction may promote the development of seizure activity. Of particular interest are studies demonstrating elevated concentrations of alpha-synuclein in the serum and cerebrospinal fluid of patients with pharmacoresistant epilepsy, which may reflect both its involvement in disease pathogenesis and its potential utility as a biomarker. There is also a rationale for investigating the role of other family members, beta- and gamma-synucleins, although currently available data is limited. Systematization and synthesis of accumulated evidence on the possible association between synucleins and epileptic processes may contribute to a more profound understanding of the molecular mechanisms of epileptogenesis, identification of novel therapeutic targets, and development of methods for early diagnosis.