Russian Journal of PhysiologyRussian Journal of PhysiologyРоссийский физиологический журнал им. И.М. Сеченова0869-81392658-655XThe Russian Academy of Sciences65171410.31857/S0869813923110079GNBBKLEXPERIMENTAL ARTICLESЭКСПЕРИМЕНТАЛЬНЫЕ СТАТЬИPharmacological Inhibition of the AQP4 Water Channel Activity Causes an Aggravation of Alpha-Synuclein Pathology in the Substantia Nigra in a Rat Model of Parkinson’s DiseaseФармакологическое ингибирование активности водного канала AQP4 вызывает усиление альфа-синуклеиновой патологии в черной субстанции в модели болезни Паркинсона у крысLapshinaK. V.ЛапшинаК. В.ksenia.lapshina@gmail.comKhaninaM. V.ХанинаМ. В.ksenia.lapshina@gmail.comKaismanovaM. P.КайсмановаМ. П.ksenia.lapshina@gmail.comEkimovaI. V.ЕкимоваИ. В.ksenia.lapshina@gmail.comSechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of SciencesИнститут эволюционной физиологии и биохимии им. И.М. Сеченова РАН01112023109111684169801022025Copyright ©; 2023, К.В. Лапшина, М.В. Ханина, М.П. Кайсманова, И.В. ЕкимоваCopyright ©; 2023, К.В. Лапшина, М.В. Ханина, М.П. Кайсманова, И.В. Екимова2023К.В. Лапшина, М.В. Ханина, М.П. Кайсманова, И.В. ЕкимоваК.В. Лапшина, М.В. Ханина, М.П. Кайсманова, И.В. Екимоваhttps://journals.eco-vector.com/0869-8139/article/view/651714

The misfolding of the protein α-synuclein, which leads to the formation of neurototoxic oligomers and aggregates, is one of the main causes of loss of dopaminergic (DA) neurons within the substantia nigra pars compacta (SNpc) in Parkinson’s disease (PD). We previously found that pharmacological inhibition of the water channel aquaporin-4 (AQP4), participating in the mechanisms of brain clearance of amyloidogenic proteins, caused the aggravation of neurodegeneration in the nigrostriatal system and the development of motor disturbances in a lactacystin model of PD. It was hypothesized that the progression of neurodegeneration can be a result of the excessive accumulation of pathologic forms of α-synuclein due to the AQP4 inhibition. The aim of this study is to determine whether pharmacological inhibition of AQP4 activity in a rat model of preclinical PD leads to an aggravation in α-synuclein pathology. The experiments were performed on male Wistar rats. AQP4 activity was suppressed using the intracerebroventricular injection of inhibitor TGN-020. To reproduce the model of the preclinical stage of PD, a specific proteasome inhibitor lactacystin (LC) was used. It was injected bilaterally into the SNpc. Immunoblotting methods and confocal microscopy were applied. The LC model of PD was characterized by a pathologic accumulation of total water-soluble and Ser129-phosphorylated forms of α-synuclein, as well as by formation of insoluble α-synuclein aggregates in the DA-neurons of SNpc. TGN-020 caused a significant aggravation of α-synuclein pathology in the LC model of PD. It was manifested by a marked increase in the level of water-soluble and modified forms of α-synuclein and by the 1.9-fold rise in the amount of α-synuclein aggregates in SN. We suppose that the disfunction of AQP4 which is involved in glymphatic system functioning, can be one of the mechanisms leading to the neurodegeneration and accumulation of amyloidogenic proteins in brain parenchyma during PD. The water channel AQP4 might be a target for the development of new therapeutic approaches aimed at attenuation of the cytotoxicity, accumulation and distribution of α-synuclein during the development of PD-like pathology.

Нарушение фолдинга белка α-синуклеина, способствующее образованию нейротоксичных олигомеров и агрегатов, является одной из основных причин гибели дофамин (ДА)-ергических нейронов компактной части черной субстанции (кчЧС) при болезни Паркинсона (БП). Ранее мы установили, что фармакологическое ингибирование активности водного канала аквапорина-4 (AQP4), участвующего в механизмах очистки мозга от амилоидогенных белков, усиливало процесс нейродегенерации в нигростриатной системе и вызывало появление моторных нарушений в лактацистиновой модели БП. Предполагается, что прогрессирование нейродегенерации происходит из-за избыточного накопления патологических форм α-синуклеина в кчЧС вследствие снижения активности AQP4. Задача данного исследования – выяснить, приводит ли фармакологическое ингибирование активности водного канала AQP4 в головном мозге к усилению α-синуклеиновой патологии в кчЧС в модели БП у крыс. Эксперименты выполнены на самцах крыс популяции Вистар. Активность AQP4 подавляли с помощью ингибитора TGN-020, вводившегося в боковой желудочек головного мозга. Для воспроизведения модели БП использовали специфический ингибитор протеасом лактацистин (ЛЦ), который вводили билатерально в кчЧС. В исследовании применены иммуноблоттинг и конфокальная микроскопия. Модель БП характеризовалась патологическим накоплением общей водорастворимой и фосфорилированной по Ser129 форм α-синуклеина в ткани кчЧС и образованием нерастворимых агрегатов α-синуклеина в ДА-ергических нейронах кчЧС. Введение TGN-020 приводило к усугублению α-синуклеиновой патологии в модели БП, проявлявшемуся повышением уровней водорастворимой и модифицированной форм α-синуклеина, а также увеличением количества агрегатов α-синуклеина в черной субстанции в 1.9 раза. Предполагается, что дисфункция AQP4 является одним из механизмов, приводящих к нейродегенерации и накоплению амилоидогенных белков в паренхиме головном мозге при БП. Водный канал AQP4 может явиться перспективной мишенью для разработки терапевтических подходов, направленных на ослабление цитотоксичности, аккумуляции и распространения α-синуклеина в головном мозге при развитии Паркинсон-подобной патологии.

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