vavilovВавиловский журнал генетики и селекцииVavilov Journal of Genetics and Breeding2500-3259Institute of Cytology and Genetics of Siberian Branch of the RAS10.18699/VJ19.507vavilov-2129Research ArticleМОЛЕКУЛЯРНАЯ И КЛЕТОЧНАЯ БИОЛОГИЯMOLECULAR AND CELL BIOLOGYРегуляторная роль цистатина С в аутофагии и нейродегенерацииThe regulatory role of cystatin C in autophagy and neurodegenerationКороленкоТ. А.KorolenkoT. A.t.a.korolenko@physiol.ruШинтяпинаА. Б.ShintyapinaA. B.ПупышевА. Б.PupyshevA. B.АкопянА. А.AkopyanA. A.РусскихГ. С.RusskikhG. S.ДиковскаяМ. А.DikovskayaM. A.

Научно-исследовательский институт биохимии, Федеральный исследовательский центр фундаментальной и трансляционной медицины; 

 

ВавилинВ. А.VavilinV. A.https://orcid.org/0000-0002-9412-3874ЗавьяловЕ. Л.ZavjalovE. LТихоноваМ. А.TikhonovaM. A.АмстиславскаяТ. Г.AmstislavskayaT. G.Научно-исследовательский институт физиологии и фундаментальной медициныРоссияScientific Research Institute of Physiology and Basic MedicineRussian FederationНаучно-исследовательский институт молекулярной биологии и биофизики, Федеральный исследовательский центр фундаментальной и трансляционной медициныРоссияScientific Research Institute of Molecular Biology and Biophysics, Federal Research Center for Basic and Translational MedicineRussian FederationНаучно-исследовательский институт биохимии, Федеральный исследовательский центр фундаментальной и трансляционной медициныРоссияScientific Research Institute of Biochemistry, Federal Research Center for Basic and Translational MedicineRussian FederationНаучно-исследовательский институт физиологии и фундаментальной медицины; НМИЦ «МНТК «Микрохирургия глаза им. акад. С.Н. Федорова», Новосибирское отделениеРоссияScientific Research Institute of Physiology and Basic Medicine; S.N. Fedorov NMRC “MNTK “Eye Microsurgery”, Novosibirsk BranchRussian FederationНаучно-исследовательский институт биохимии, Федеральный исследовательский центр фундаментальной и трансляционной медицины; Федеральный исследовательский центр Институт цитологии и генетики Сибирского отделения Российской академии наукРоссияScientific Research Institute of Molecular Biology and Biophysics, Federal Research Center for Basic and Translational Medicine; Institute of Cytology and Genetics, SB RASRussian FederationНаучно-исследовательский институт биохимии, Федеральный исследовательский центр фундаментальной и трансляционной медициныРоссияInstitute of Cytology and Genetics, SB RASRussian FederationНаучно-исследовательский институт физиологии и фундаментальной медицины; Новосибирский национальный исследовательский государственный университетРоссияScientific Research Institute of Physiology and Basic Medicine; Novosibirsk State UniversityRussian Federation201905072019234390397Copyright © Короленко Т.А., Шинтяпина А.Б., Пупышев А.Б., Акопян А.А., Русских Г.С., Диковская М.А., Вавилин В.А., Завьялов Е.Л., Тихонова М.А., Амстиславская Т.Г., 20192019Короленко Т.А., Шинтяпина А.Б., Пупышев А.Б., Акопян А.А., Русских Г.С., Диковская М.А., Вавилин В.А., Завьялов Е.Л., Тихонова М.А., Амстиславская Т.Г.Korolenko T.A., Shintyapina A.B., Pupyshev A.B., Akopyan A.A., Russkikh G.S., Dikovskaya M.A., Vavilin V.A., Zavjalov E.L., Tikhonova M.A., Amstislavskaya T.G.This work is licensed under a Creative Commons Attribution 4.0 License.https://vavilov.elpub.ru/jour/article/view/2129

Aутофагия – динамичный клеточный процесс, связанный с оборотом белков, белковых комплексов и органелл посредством лизосомной деградации. Аутофагия особенно важна в нейронах, которые не имеют пролиферативного ресурса для клеточного восстановления. Одним из мощных регуляторов аутофагии является цистатин С. Изменения экспрессии и секреции цистатина С в головном мозге показаны при боковом амиотрофическом склерозе, болезни Альцгеймера и Паркинсона, а также на некоторых моделях нейродегенерации у животных, что подтверждает защитную функцию цистатина С. Высказано предположение, что цистатин С играет важную роль в амилоидогенезе и может рассматриваться как возможное терапевтическое средство для предупреждения и лечения ряда нейродегенеративных заболеваний (болезни Альцгеймера и Паркинсона). Цистатин С колокализуется с амилоидом β в головном мозге при болезни Альцгеймера. Контролируемая экспрессия пептида цистатина С предложена в качестве нового подхода к терапии болезни Альцгеймера. При болезни Паркинсона уровни цистатина С в сыворотке крови могут прогнозировать тяжесть заболевания и когнитивную дисфункцию, хотя конкретное участие цистатина С остается неясным. Рассмотрена роль цистатина С в нейродегенерации и проведена оценка результатов в связи с активностью аутофагии. У здоровых людей обнаружена высокая концентрация цистатина С в спинномозговой жидкости по сравнению с сывороткой крови; значительно более низкие концентрации наблюдали в других биологических жидкостях (внутриглазная жидкость, желчь, пот). При оценке влияния возраста обнаружено повышение концентрации цистатина С как в сыворотке, так и во внутриглазной жидкости у пожилых людей (61–80 лет) по сравнению с практически здоровыми людьми в возрасте 40–60 лет. В эксперименте на мышах C57Bl/6J концентрация цистатина С была значительно выше в мозговой ткани, чем в печени и селезенке, что указывает на важную функцию этого ингибитора цистеиновых протеаз в головном мозге. На трансгенной мышиной модели болезни Паркинсона (5 месяцев) найдено значительное увеличение осмотической чувствительности лизосом мозга, соответствующее усилению аутофагии, тогда как на мышиной модели болезни Альцгеймера этот показатель не обнаружил изменения аутофагии.

Autophagy is a dynamic cellular process involved in the turnover of proteins, protein complexes, and organelles through lysosomal degradation. It is particularly important in neurons, which do not have a proliferative option for cellular repair. Autophagy has been shown to be suppressed in the striatum of a transgenic mouse model of Parkinson’s disease. Cystatin C is one of the potent regulators of autophagy. Changes in the expression and secretion of cystatin C in the brain have been shown in amyotrophic lateral sclerosis, Alzheimer’s and Parkinson’s diseases, and in some animal models of neurodegeneration, thus proving a protective function of cystatin C. It has been suggested that cystatin C plays the primary role in amyloidogenesis and shows promise as a therapeutic agent for neurodegenerative diseases (Alzheimer’s and Parkinson’s diseases). Cystatin C colocalizes with the amyloid β-protein in the brain during Alzheimer’s disease. Controlled expression of a cystatin C peptide has been proposed as a new approach to therapy for Alzheimer’s disease. In Parkinson’s disease, serum cystatin C levels can predict disease severity and cognitive dysfunction, although the exact involvement of cystatin C remains unclear. The aim: to study the role of cystatin C in neurodegeneration and evaluate the results in relation to the mechanism of autophagy. In our study on humans, a higher concentration of cystatin C was noted in cerebrospinal fluid than in serum; much lower concentrations were observed in other biological fluids (intraocular fluid, bile, and sweat). In elderly persons (61–80 years old compared to practically healthy people at 40–60 years of age), we revealed increased cystatin C levels both in serum and intraocular fluid. In an experiment on C57Bl/6J mice, cystatin C concentration was significantly higher in brain tissue than in the liver and spleen: an indication of an important function of this cysteine protease inhibitor in the brain. Using a transgenic mouse model of Parkinson’s disease (5 months old), we demonstrated a significant increase in osmotic susceptibility of brain lysosomes, depending on autophagy, while in a murine model of Alzheimer’s disease, this parameter did not differ from that in the appropriate control.

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The authors declare that there are no conflicts of interest present.