Dysregulation of intraocular pressure (IOP) is one of the main risk factors for glaucoma. γ-synuclein is a member of the synuclein family of widely expressed synaptic proteins within the central nervous system that are implicated in certain types of neurodegeneration. γ-synuclein expression and localization changes in the retina and optic nerve of patients with glaucoma. However, the mechanisms by which γ-synuclein could contribute to glaucoma are poorly understood. We assessed the presence of autoantibodies to γ-synuclein in the blood serum of patients with primary open-angle glaucoma (POAG) by immunoblotting. A positive reaction was detected for five out of 25 patients (20%) with POAG. Autoantibodies to γ-synuclein were not detected in a group of patients without glaucoma. We studied the dynamics of IOP in response to IOP regulators in knockout mice (γ-KO) to understand a possible link between γ-synuclein dysfunction and glaucoma-related pathophysiological changes. The most prominent decrease of IOP in γ-KO mice was observed after the instillation of 1% phenylephrine and 10% dopamine. The total protein concentration in tear fluid of γ-KO mice was approximately two times higher than that of wild-type mice, and the activity of neurodegeneration-linked protein α2-macroglobulin was reduced. Therefore, γ-synuclein dysfunction contributes to pathological processes in glaucoma, including dysregulation of IOP.

Synucleins comprise a family of small proteins highly expressed in the nervous system of vertebrates and involved in various intraneuronal processes. The malfunction of alpha-synuclein is one of the key events in pathogenesis of Parkinson disease and certain other neurodegenerative diseases, and there is a growing body of evidence that malfunction of other two synucleins might be involved in pathological processes in the nervous system. The modulation of various presynaptic mechanisms of neurotransmission is an important function of synucleins, and therefore, it is feasible that their deficiency might affect global electrical activity detected of the brain. However, the effects of the loss of synucleins on the frequency spectra of electroencephalograms (EEGs) have not been systematically studied so far. In the current study, we assessed changes in such spectra in single-, double- and triple-knockout mice lacking alpha-, beta- and gamma-synucleins in all possible combinations. EEGs were recorded from the motor cortex, the putamen, the ventral tegmental area and the substantia nigra of 78 3-month-old male mice from seven knockout groups maintained on the C57BL/6J genetic background, and 10 wild-type C57BL/6J mice for 30 min before and for 60 min after the systemic injection of a DA receptor agonist, apomorphine (APO). We found that almost any variant of synuclein deficiency causes multiple changes in both basal and APO-induced EEG oscillation profiles. Therefore, it is not the absence of any particular synuclein but rather a disbalance of synucleins that causes widespread changes in EEG spectral profiles.

Background: The three Synuclein family members (α-, β-, and γ-synuclein) are presynaptic proteins that regulate synaptic vesicle trafficking and thereby influence neurotransmitter release. Synucleins belong to a class of intrinsically disordered proteins and are prone to aggregation into pathological deposits, which may impair their physiological synaptic functions. Knockout (KO) mouse lines, commonly used to model synuclein depletion in the nervous system, reveal a range of phenotypes with different motor and behavioral deficits. However, given the high sequence homology and functional interplay among the three synucleins, the specific contribution of each family member to these phenotypes remains poorly understood. Objective: In this study, we conducted a comparative phenotypic analysis of γ-synuclein KO, α- and β-synuclein KO, and αβγ-synuclein KO mice. Methods: Mice were subjected to a battery of behavioral tests assessing motor activity and coordination, anxiety-like behavior, and spatial learning and memory. Synaptic vesicle proteins were analyzed in brain tissues using Western blotting. Results: We observed that knocking out γ-synuclein but not α- and β-synucleins reduces mouse lifespan and leads to sustained reduction in muscle strength implicating that γ-synuclein is essential for longevity and motor system function. Another consequence of γ-synuclein deficiency is altered anxiety-like behavior manifested as a diminished aversive response, while exploratory behavior and memory remain intact. The triple KO mice mirror γ-synuclein KO mice in some behavioral changes, including shortened lifespan, reduced muscle strength, and decreased anxiety-like behavior. However, the triple KO mice additionally exhibit hyperactivity, which is not present in the other groups. No changes in synaptic vesicle marker levels were detected, indicating that the observed motor and behavioral abnormalities are not attributable to impaired synaptic connectivity. Conclusions: Taken together, these findings demonstrate nonredundant functions of individual synuclein family members and highlight a distinct role of γ-synuclein in regulating motor performance and behavioral responses.

Актуальность. Нарушение дофаминовой нейротрансмиссии характерно для многих нейродегенеративных заболеваний с моторной дисфункцией. Участие белков-синуклеинов в регуляции гомеостаза дофамина делает актуальным их изучение в контексте патологии. Целью исследования является характеристика изменений моторной функции мышей с различными комбинациями нокаутов по генам белков семейства синуклеинов с возрастом. Материалы и методы. Восемь групп животных проходили тестирование в автоматизированной системе CatWalk XT, а их мышечная сила оценивалась с помощью теста «Сила хвата» (Grip Strength Test Meter) в возрасте 6, 12, 18 и 24 месяца. Статистическая обработка данных проводилась в программе «GraphPad Prism Software 7.0». Результаты. Было выявлено достоверное снижение параметра «длина следа» с возрастом в группах животных без функционального альфа-синуклеина. Также у этих животных отмечены и другие нарушения походки. По данным нашего исследования, отсутствие бета- и гамма-синуклеина приводит к достоверному снижению массы тела и ухудшению силы хвата. Заключение. Показана важная роль белков семейства синуклеинов в ухудшении двигательной функции животных с возрастом и выявлены некоторые скрытые параметры, вносящие изменения в походку животных с различным комбинациями нокаутов по генам белков семейства синуклеинов. Actuality. Dopamine neurotransmission impairment is a common phenomenon in neurodegenerative diseases associated with motor dysfunction. The involvement of synuclein proteins in the regulation of dopamine homeostasis renders their study pertinent in the context of pathology. The aim of this study is to identify the impact of different combinations on motor function developed with ageing, in knockouts of synuclein family genes. Materials and methods. Eight groups of animals were tested in the CatWalk XT automated system, and their muscle strength was evaluated using the Grip Strength Test Meter at 6, 12, 18 and 24 months of age. Statistical analysis was carried out using GraphPad Prism Software 7.0. Results. A significant reduction in the ‘print length’ parameter with age was observed in the groups of animals lacking functional alpha-synuclein. Furthermore, other gait abnormalities were observed in these animals. Our study indicates that the absence of beta- and gamma-synuclein is associated with a significant reduction in body weight and impaired grip strength. Conclusion. The present study has demonstrated the pivotal role of synuclein family proteins in the impairment of motor function in animals with age. Furthermore, it has identified several hidden parameters that introduce changes in the gait of animals with different combinations of synuclein genes knockouts.

BACKGROUND: Treatment of deep chronic wounds with the bone tissue involvement against the background of lower limb atherosclerosis and diabetic foot syndrome does not fit any reasonable hospital stay duration and at the same time has no effective outpatient methods. Therapy with conditioned medium derived from human mesenchymal stem cells (CM-MSC) may be a solution for this problem. CLINICAL CASE DESCRIPTION: Patient F., 77-year-old, arrived for an outpatient treatment of local necrosis in the area of the 1st toe of the left foot in April, 2022. The main diagnosis: Peripheral arterial disease of the lower extremities. Multifocal atherosclerosis. Occlusion of the superficial femoral and popliteal arteries, diffuse lesions of the lower leg arteries on the left. Chronic arterial insufficiency of the 4th degree. Attempts of revascularisation of the left lower limb. Limited gangrene (Wagner IV) of the 1st toe of the left foot. Associated diseases: insulin-dependent type 2 diabetes mellitus (for more than 30 years). Diabetic polyneuropathy. Diabetic foot syndrome, neurotrophic form. Local treatment was performed by the microsurgical debridement of the affected surface in combination with the method of multilayered dressings, according to the previously patented technology. The microsurgical treatment of the bone surface in the wound area was carried out with the use of CM-MSC. Positive dynamics in the form of a partial closure of the bone fragment with soft tissue was observed on the sixth month of therapy. The complete closure of the open bone fragment was observed in 12 months from the beginning of the outpatient treatment. CONCLUSION: The developed method of treatment using CM-MSC can be effective for chronic wounds with open bone surfaces.

Background: The three Synuclein family members (α-, β-, and γ-synuclein) are presynaptic proteins that regulate synaptic vesicle trafficking and thereby influence neurotransmitter release. Synucleins belong to a class of intrinsically disordered proteins and are prone to aggregation into pathological deposits, which may impair their physiological synaptic functions. Knockout (KO) mouse lines, commonly used to model synuclein depletion in the nervous system, reveal a range of phenotypes with different motor and behavioral deficits. However, given the high sequence homology and functional interplay among the three synucleins, the specific contribution of each family member to these phenotypes remains poorly understood. Objective: In this study, we conducted a comparative phenotypic analysis of γ-synuclein KO, α- and β-synuclein KO, and αβγ-synuclein KO mice. Methods: Mice were subjected to a battery of behavioral tests assessing motor activity and coordination, anxiety-like behavior, and spatial learning and memory. Synaptic vesicle proteins were analyzed in brain tissues using Western blotting. Results: We observed that knocking out γ-synuclein but not α- and β-synucleins reduces mouse lifespan and leads to sustained reduction in muscle strength implicating that γ-synuclein is essential for neuromuscular function. Another consequence of γ-synuclein deficiency is altered anxiety-like behavior manifested as a diminished aversive response, while exploratory behavior and memory remain intact. The triple KO mice mirror γ-synuclein KO mice in some behavioral changes, including shortened lifespan, reduced muscle strength, and decreased anxiety-like behavior. However, the triple KO mice additionally exhibit hyperactivity, which is not present in the other groups. No changes in synaptic vesicle marker levels were detected, indicating that the observed motor and behavioral abnormalities are not attributable to impaired synaptic connectivity. Conclusions: Taken together, these findings demonstrate nonredundant functions of individual synuclein family members and highlight a distinct role of γ-synuclein in regulating motor performance and behavioral responses.