vavilovВавиловский журнал генетики и селекцииVavilov Journal of Genetics and Breeding2500-3259Institute of Cytology and Genetics of Siberian Branch of the RAS10.18699/vjgb-25-89vavilov-4809Research ArticleМЕДИЦИНСКАЯ ГЕНЕТИКАMEDICAL GENETICSАссоциация варианта rs823144 гена RAB29 с активностью лизосомных гидролаз в клетках крови и риском болезни ПаркинсонаAssociation of the rs823144 variant of the RAB29 gene with the activity of lysosomal hydrolases in blood cells and risk of Parkinson’s diseaseБашароваК. С.BasharovaK. S.

 Гатчина 

 Санкт-Петербург 

Gatchina 

St. Petersburg 

kbasharova@yandex.ruБезруковаА. И.BezrukovaA. I.

 Гатчина 

 Санкт-Петербург 

 Gatchina 

 St. Petersburg 

СенкевичК. А.SenkevichK. A.

 Монреаль 

  Montreal 

 

БайдаковаГ. В.BaydakovaG. V.

 Москва 

 Moscow 

РыбаковА. В.RybakovA. V.

 Санкт-Петербург 

 St. Petersburg 

МилюхинаИ. В.MiliukhinaI. V.

 Гатчина 

 Санкт-Петербург 

 Gatchina 

 St. Petersburg 

ТимофееваА. А.TimofeevaA. A.

 Санкт-Петербург 

 St. Petersburg 

ЗахароваЕ. Ю.ZakharovaE. Yu.

 Гатчина 

 Москва 

 Gatchina 

 Moscow 

ПчелинаС. Н.PchelinaS. N.

 Гатчина 

 Gatchina 

 St. Petersburg 

УсенкоТ. С.UsenkoT. S.

 Гатчина 

 Gatchina 

 St. Petersburg 

usenko_ts@pnpi.nrcki.ruПетербургский институт ядерной физики им. Б.П. Константинова Национального исследовательского центра «Курчатовский институт»; Первый Санкт-Петербургский государственный медицинский университет им. акад. И.П. ПавловаРоссияPetersburg Nuclear Physics Institute named by B.P. Konstantinov of National Research Centre “Kurchatov Institute”; Pavlov First Saint Petersburg State Medical UniversityRussian FederationМонреальский неврологический институт при Университете МакгиллаКанадаMontreal Neurological Institute, McGill UniversityCanadaМедико-генетический научный центр им. акад. Н.П. БочковаРоссияBochkov Research Centre for Medical GeneticsRussian FederationИнститут мозга человека им. Н.П. Бехтеревой Российской академии наукРоссияN.P. Bechtereva Institute of the Human Brain of the Russian Academy of SciencesRussian FederationПетербургский институт ядерной физики им. Б.П. Константинова Национального исследовательского центра «Курчатовский институт»; Институт мозга человека им. Н.П. Бехтеревой Российской академии наукРоссияPetersburg Nuclear Physics Institute named by B.P. Konstantinov of National Research Centre “Kurchatov Institute”; N.P. Bechtereva Institute of the Human Brain of the Russian Academy of SciencesRussian FederationПервый Санкт-Петербургский государственный медицинский университет им. акад. И.П. ПавловаРоссияPavlov First Saint Petersburg State Medical UniversityRussian FederationПетербургский институт ядерной физики им. Б.П. Константинова Национального исследовательского центра «Курчатовский институт»; Медико-генетический научный центр им. акад. Н.П. БочковаРоссияPetersburg Nuclear Physics Institute named by B.P. Konstantinov of National Research Centre “Kurchatov Institute”; Bochkov Research Centre for Medical GeneticsRussian Federation202509102025296819827Copyright © Башарова К.С., Безрукова А.И., Сенкевич К.А., Байдакова Г.В., Рыбаков А.В., Милюхина И.В., Тимофеева А.А., Захарова Е.Ю., Пчелина С.Н., Усенко Т.С., 20252025Башарова К.С., Безрукова А.И., Сенкевич К.А., Байдакова Г.В., Рыбаков А.В., Милюхина И.В., Тимофеева А.А., Захарова Е.Ю., Пчелина С.Н., Усенко Т.С.Basharova K.S., Bezrukova A.I., Senkevich K.A., Baydakova G.V., Rybakov A.V., Miliukhina I.V., Timofeeva A.A., Zakharova E.Y., Pchelina S.N., Usenko T.S.This work is licensed under a Creative Commons Attribution 4.0 License.https://vavilov.elpub.ru/jour/article/view/4809

Геномные исследования последних лет выявили ассоциацию гена RAB29 с болезнью Паркинсона (БП). Белок Rab29, кодируемый геном RAB29, – один из регуляторов богатой лейциновыми повторами киназы 2 (LRRK2). Мутации в гене LRRK2 ассоциированы с увеличением киназной активности LRRK2 и приводят к развитию аутосомно-доминантных форм БП. Недавно показано, что изменение киназной активности LRRK2 может быть связано с изменением активности лизосомных гидролаз и концентрации лизосфинголипидов. Цель данного исследования заключалась в оценке ассоциации rs823144 в промоторе гена RAB29 с БП с экспрессией гена RAB29, активностью лизосомных гидролаз и концентрацией лизосфинголипидов в крови при БП. В ходе исследования проведены скрининг варианта rs823144 гена RAB29 в группе пациентов с БП (N = 903) и в контроле (N = 618) с использованием методов массового параллельного секвенирования и полимеразная цепная реакция (ПЦР) с последующим рестрикционным анализом. Экспрессия гена RAB29 оценивалась в мононуклеарах периферической крови методом ПЦР в режиме реального времени. Активности лизосомных гидролаз (глюкоцереброзидаза (GCase), альфа-галактозидаза (GLA), кислая сфингомиелиназа (ASMase), галактозилцереброзидаза (GALC)) и концентрации лизосфинголипидов (глоботриаозилсфингозин (LysoGb3), сфингомиелин (LysoSM), гексозилсфингозин (HexSph)) оценивались в крови методом высокоэффективной жидкостной хроматографии с тандемной масс-спектрометрией (ВЭЖХ-МС/МС). Аллель С rs823144 гена RAB29 ассоциирован с пониженным риском БП в северо-западной популяции Российской Федерации (ОШ: 0.7806, 95 % ДИ: 0.6578–0.9263, p = 0.0046), что соответствует мировым данным. Однако в ходе работы не выявлено ассоциации аллеля С rs823144 гена RAB29 с уровнем мРНК гена RAB29 в мононуклеарах периферической крови. В то же время носительство аллеля С rs823144 было ассоциировано с повышенной активностью GLA и сниженной концентрацией LysoGb3 в крови при БП. Таким образом, нами впервые показана ассоциация аллеля С rs823144 гена RAB29 с пониженным риском БП в северо-западной популяции Российской Федерации. Аллель С rs823144 ассоциирован с повышенной активностью GLA и сниженной концентрацией LysoGb3 в крови при БП. Полученные результаты позволяют предположить ассоциацию гена RAB29 с метаболизмом сфинголипидов.

Recent genome-wide association studies have identified a link between the RAB29 gene and Parkinson’s disease (PD). The Rab29 protein encoded by RAB29 regulates leucine-rich repeat kinase 2 (LRRK2). Mutations in the LRRK2 gene increase its kinase activity and contribute to autosomal dominant forms of PD. Previous research has shown that altered LRRK2 kinase activity may correlate with the activity of lysosomal hydrolases and the concentration of sphingolipids. This study aimed to assess the association of the rs823144 variant in the promoter region of the RAB29 gene with PD risk, and to evaluate RAB29 expression, lysosomal hydrolase activity, and sphingolipid concentrations in the blood of PD patients. We screened the rs823144 variant of the RAB29 gene in a cohort of PD patients (N = 903) and controls (N = 618) using next-generation sequencing (NGS) and polymerase chain reaction (PCR) followed by restriction fragment length polymorphism analysis. The expression of the RAB29 gene was measured in peripheral blood mononuclear cells (PBMCs) using qPCR. We assessed the activities of lysosomal hydrolases (glucocerebrosidase (GCase), alpha-galactosidase (GLA), acid sphingomyelinase (ASMase), and galactosylcerebrosidase (GALC)) and the concentrations of sphingolipids (globotriaosylsphingosine (LysoGb3), sphingomyelin (LysoSM), and hexosylsphingosine (HexSph)) in blood using high-performance liquid chromatography with tandem mass spectrometry (HPLC-MS/MS). The RAB29 rs823144 C allele was associated with a reduced risk of PD in the Northwestern Russian population (OR = 0.7806, 95 % CI: 0.6578–0.9263, p = 0.0046), which is consistent with global data. However, no significant association was observed between the rs823144 C allele and RAB29 mRNA expression in PBMCs. Notably, the C allele was associated with increased GLA activity and decreased concentrations of LysoGb3 and LysoSM in the blood of PD patients. In conclusion, we demonstrate for the first time an association between the RAB29 rs823144 C allele and a reduced risk of PD in the Northwestern Russian population. Moreover, the RAB29 rs823144 C allele is associated with altered lysosomal enzyme activity and sphingolipid profiles, suggesting a potential role of RAB29 in sphingolipid metabolism relevant to PD pathogenesis.

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