title: ÐÑÐµÐ½ÐºÐ° Ð²Ð»Ð¸ÑÐ½Ð¸Ñ Ð¸Ð½Ð³Ð¸Ð±Ð¸ÑÐ¾Ð²Ð°Ð½Ð¸Ñ ÐºÐ¸Ð½Ð°Ð·Ð½Ð¾Ð¹ Ð°ÐºÑÐ¸Ð²Ð½Ð¾ÑÑÐ¸ Ð¾Ð±Ð¾Ð³Ð°ÑÐµÐ½Ð½Ð¾Ð¹ Ð»ÐµÐ¹ÑÐ¸Ð½Ð¾Ð²ÑÐ¼Ð¸ Ð¿Ð¾Ð²ÑÐ¾ÑÐ°Ð¼Ð¸ ÐºÐ¸Ð½Ð°Ð·Ñ 2 (LRRK2) Ð½Ð° Ð»Ð¸Ð·Ð¾ÑÐ¾Ð¼Ð½ÑÑ Ð°ÐºÑÐ¸Ð²Ð½Ð¾ÑÑÑ Ð¿ÐµÑÐ²Ð¸ÑÐ½Ð¾Ð¹ ÐºÑÐ»ÑÑÑÑÑ Ð¼Ð°ÐºÑÐ¾ÑÐ°Ð³Ð¾Ð² Ð¿ÐµÑÐ¸ÑÐµÑÐ¸ÑÐµÑÐºÐ¾Ð¹ ÐºÑÐ¾Ð²Ð¸ Ð¿Ð°ÑÐ¸ÐµÐ½ÑÐ¾Ð² Ñ ÑÐ¸Ð½ÑÐºÐ»ÐµÐ¸Ð½Ð¾Ð¿Ð°ÑÐ¸ÑÐ¼Ð¸
title: Ð²ÑÐ¿ÑÑÐºÐ½Ð°Ñ ÐºÐ²Ð°Ð»Ð¸ÑÐ¸ÐºÐ°ÑÐ¸Ð¾Ð½Ð½Ð°Ñ ÑÐ°Ð±Ð¾ÑÐ° Ð±Ð°ÐºÐ°Ð»Ð°Ð²ÑÐ°
titleType: Subtitle
title: Evaluation of the effect of inhibition of kinase activity of leucine-rich repeat kinase 2 (lrrk2) on lysosomal activity of primary culture of peripheral blood macrophages from patients with synucleinopathies
Creators: name: ÐÐ°Ð³Ð°Ð½Ð¾Ð²Ð°, ÐÐ°ÑÑÑ
Publisher: name: Ð¡Ð°Ð½ÐºÑ-ÐÐµÑÐµÑÐ±ÑÑÐ³ÑÐºÐ¸Ð¹ Ð¿Ð¾Ð»Ð¸ÑÐµÑÐ½Ð¸ÑÐµÑÐºÐ¸Ð¹ ÑÐ½Ð¸Ð²ÐµÑÑÐ¸ÑÐµÑ ÐÐµÑÑÐ° ÐÐµÐ»Ð¸ÐºÐ¾Ð³Ð¾
Year: 2024
Subjects: Ð±Ð¾Ð»ÐµÐ·Ð½Ñ ÐÐ°ÑÐºÐ¸Ð½ÑÐ¾Ð½Ð°
Ð´ÐµÐ¼ÐµÐ½ÑÐ¸Ñ Ñ ÑÐµÐ»ÑÑÐ°Ð¼Ð¸ ÐÐµÐ²Ð¸
Ð¼Ð½Ð¾Ð¶ÐµÑÑÐ²ÐµÐ½Ð½Ð°Ñ ÑÐ¸ÑÑÐµÐ¼Ð½Ð°Ñ Ð°ÑÑÐ¾ÑÐ¸Ñ
Ð°Ð»ÑÑÐ°-ÑÐ¸Ð½ÑÐºÐ»ÐµÐ¸Ð½
LRRK2
Ð³Ð»ÑÐºÐ¾ÑÐµÑÐµÐ±ÑÐ¾Ð·Ð¸Ð´Ð°Ð·Ð°
Ð³Ð»ÑÐºÐ¾Ð·Ð¸Ð»ÑÑÐ¸Ð½Ð³Ð¾Ð·Ð¸Ð½
p62
LC3-II
Parkinsons disease
dementia with Lewy bodies
multiple system atrophy
alpha-synuclein
glucocerebrosidase
glucosylsphingosine

description: ÐÐ°Ð½Ð½Ð°Ñ ÑÐ°Ð±Ð¾ÑÐ° Ð¿Ð¾ÑÐ²ÑÑÐµÐ½Ð° Ð¾ÑÐµÐ½ÐºÐµ Ð²Ð»Ð¸ÑÐ½Ð¸Ñ Ð¸Ð½Ð³Ð¸Ð±Ð¸ÑÐ¾Ð²Ð°Ð½Ð¸Ñ ÐºÐ¸Ð½Ð°Ð·Ð½Ð¾Ð¹ Ð°ÐºÑÐ¸Ð²Ð½Ð¾ÑÑÐ¸ Ð±Ð¾Ð³Ð°ÑÐ¾Ð¹ Ð»ÐµÐ¹ÑÐ¸Ð½Ð¾Ð²ÑÐ¼Ð¸ Ð¿Ð¾Ð²ÑÐ¾ÑÐ°Ð¼Ð¸ ÐºÐ¸Ð½Ð°Ð·Ñ 2 (LRRK2) Ð½Ð° Ð»Ð¸Ð·Ð¾ÑÐ¾Ð¼Ð½ÑÑ Ð°ÐºÑÐ¸Ð²Ð½Ð¾ÑÑÑ Ð² Ð¿ÐµÑÐ²Ð¸ÑÐ½Ð¾Ð¹ ÐºÑÐ»ÑÑÑÑÐµ Ð¼Ð°ÐºÑÐ¾ÑÐ°Ð³Ð¾Ð² Ð¿ÐµÑÐ¸ÑÐµÑÐ¸ÑÐµÑÐºÐ¾Ð¹ ÐºÑÐ¾Ð²Ð¸ (ÐÐÐÐÐ) Ð¿Ð°ÑÐ¸ÐµÐ½ÑÐ¾Ð² ÑÐ¾ ÑÐ¿Ð¾ÑÐ°Ð´Ð¸ÑÐµÑÐºÐ¾Ð¹ Ð±Ð¾Ð»ÐµÐ·Ð½ÑÑ ÐÐ°ÑÐºÐ¸Ð½ÑÐ¾Ð½Ð° (ÑÐÐ), Ð´ÐµÐ¼ÐµÐ½ÑÐ¸ÐµÐ¹ Ñ ÑÐµÐ»ÑÑÐ°Ð¼Ð¸ ÐÐµÐ²Ð¸ (ÐÐ¢Ð) Ð¸ Ð¼Ð½Ð¾Ð¶ÐµÑÑÐ²ÐµÐ½Ð½Ð¾Ð¹ ÑÐ¸ÑÑÐµÐ¼Ð½Ð¾Ð¹ Ð°ÑÑÐ¾ÑÐ¸ÐµÐ¹ (ÐÐ¡Ð). Ð ÑÐ¾Ð´Ðµ ÑÐ°Ð±Ð¾ÑÑ Ð±ÑÐ»Ð° Ð¿Ð¾Ð»ÑÑÐµÐ½Ð° Ð¸ ÐºÑÐ»ÑÑÐ¸Ð²Ð¸ÑÐ¾Ð²Ð°Ð½Ð° ÐÐÐÐÐ Ð¿Ð°ÑÐ¸ÐµÐ½ÑÐ¾Ð² ÑÐ¾ ÑÐÐ, ÐÐ¢Ð, ÐÐ¡Ð Ð¸ ÐºÐ¾Ð½ÑÑÐ¾Ð»Ñ Ð² Ð¿ÑÐ¸ÑÑÑÑÑÐ²Ð¸Ð¸ Ð¸ Ð±ÐµÐ· ÑÐµÐ»ÐµÐºÑÐ¸Ð²Ð½Ð¾Ð³Ð¾ Ð¸Ð½Ð³Ð¸Ð±Ð¸ÑÐ¾ÑÐ° ÐºÐ¸Ð½Ð°Ð·Ð½Ð¾Ð¹ Ð°ÐºÑÐ¸Ð²Ð½Ð¾ÑÑÐ¸ LRRK2 MLi-2, Ð¾ÑÐµÐ½ÐµÐ½Ð¾ Ð²Ð»Ð¸ÑÐ½Ð¸Ðµ Ð¸Ð½Ð³Ð¸Ð±Ð¸ÑÐ¾Ð²Ð°Ð½Ð¸Ñ ÐºÐ¸Ð½Ð°Ð·Ð½Ð¾Ð¹ Ð°ÐºÑÐ¸Ð²Ð½Ð¾ÑÑÐ¸ LRRK2 Ð½Ð° Ð°ÐºÑÐ¸Ð²Ð½Ð¾ÑÑÑ Ð»Ð¸Ð·Ð¾ÑÐ¾Ð¼Ð½Ð¾Ð³Ð¾ ÑÐµÑÐ¼ÐµÐ½ÑÐ° Ð³Ð»ÑÐºÐ¾ÑÐµÑÐµÐ±ÑÐ¾Ð·Ð¸Ð´Ð°Ð·Ñ (GCase) Ð¸ ÑÑÐ±ÑÑÑÐ°ÑÐ° Ð³Ð»ÑÐºÐ¾Ð·Ð¸Ð»ÑÑÐ¸Ð½Ð³Ð¾Ð·Ð¸Ð½Ð° (HexSph) Ð¼ÐµÑÐ¾Ð´Ð¾Ð¼ Ð²ÑÑÐ¾ÐºÐ¾ÑÑÑÐµÐºÑÐ¸Ð²Ð½Ð¾Ð¹ Ð¶Ð¸Ð´ÐºÐ¾ÑÑÐ½Ð¾Ð¹ ÑÑÐ¾Ð¼Ð°ÑÐ¾Ð³ÑÐ°ÑÐ¸Ð¸ Ð² ÑÐ¾ÑÐµÑÐ°Ð½Ð¸Ð¸ Ñ ÑÐ°Ð½Ð´ÐµÐ¼Ð½Ð¾Ð¹ Ð¼Ð°ÑÑ-ÑÐ¿ÐµÐºÑÑÐ¾Ð¼ÐµÑÑÐ¸ÐµÐ¹ Ð¸ Ð½Ð° Ð¾ÑÐ½Ð¾ÑÐ¸ÑÐµÐ»ÑÐ½ÑÐ¹ ÑÑÐ¾Ð²ÐµÐ½Ñ Ð±ÐµÐ»ÐºÐ¾Ð² p62 Ð¸ LC3-II Ð¼ÐµÑÐ¾Ð´Ð¾Ð¼ Ð²ÐµÑÑÐµÑÐ½-Ð±Ð»Ð¾ÑÑÐ¸Ð½Ð³Ð° Ð² ÐÐÐÐÐ Ð¿Ð°ÑÐ¸ÐµÐ½ÑÐ¾Ð² ÑÐ¾ ÑÐÐ, ÐÐ¢Ð, ÐÐ¡Ð Ð¸ ÐºÐ¾Ð½ÑÑÐ¾Ð»Ñ. Ð¢Ð°ÐºÐ¶Ðµ Ð² ÑÐ°Ð±Ð¾ÑÐµ Ð²Ð¿ÐµÑÐ²ÑÐµ Ð±ÑÐ»Ð¾ Ð¿Ð¾ÐºÐ°Ð·Ð°Ð½Ð¾ Ð²Ð»Ð¸ÑÐ½Ð¸Ðµ Ð¸Ð½Ð³Ð¸Ð±Ð¸ÑÐ¾Ð²Ð°Ð½Ð¸Ñ ÐºÐ¸Ð½Ð°Ð·Ð½Ð¾Ð¹ Ð°ÐºÑÐ¸Ð²Ð½Ð¾ÑÑÐ¸ LRRK2 Ð½Ð° Ð¾ÑÐ½Ð¾ÑÐ¸ÑÐµÐ»ÑÐ½ÑÐ¹ ÑÑÐ¾Ð²ÐµÐ½Ñ GCase Ð¿Ð°ÑÐ¸ÐµÐ½ÑÐ¾Ð² ÑÐ¾ ÑÐÐ. Ð­ÑÑÐµÐºÑÐ¸Ð²Ð½Ð¾ÑÑÑ Ð¸Ð½Ð³Ð¸Ð±Ð¸ÑÐ¾Ð²Ð°Ð½Ð¸Ñ ÐºÐ¸Ð½Ð°Ð·Ð½Ð¾Ð¹ Ð°ÐºÑÐ¸Ð²Ð½Ð¾ÑÑÐ¸ Ð±ÑÐ»Ð° Ð¿Ð¾Ð´ÑÐ²ÐµÑÐ¶Ð´ÐµÐ½Ð° Ð´ÐµÐ¹ÑÑÐ²Ð¸ÐµÐ¼ MLi-2 Ð½Ð° Ð±ÐµÐ»Ð¾Ðº pT73-Rab10. Ð ÑÐµÐ·ÑÐ»ÑÑÐ°ÑÐµ ÑÐ°Ð±Ð¾ÑÑ Ð±ÑÐ»Ð¾ Ð¿Ð¾ÐºÐ°Ð·Ð°Ð½Ð¾ ÑÐ½Ð¸Ð¶ÐµÐ½Ð¸Ðµ Ð°ÐºÑÐ¸Ð²Ð½Ð¾ÑÑÐ¸ GCase Ñ Ð¿Ð°ÑÐ¸ÐµÐ½ÑÐ¾Ð² Ñ ÐÐ¡Ð Ð¸ ÑÐ²ÐµÐ»Ð¸ÑÐµÐ½Ð¸Ðµ ÐºÐ¾Ð½ÑÐµÐ½ÑÑÐ°ÑÐ¸Ð¸ HexSph Ñ Ð¿Ð°ÑÐ¸ÐµÐ½ÑÐ¾Ð² ÑÐ¾ ÑÐÐ, ÐÐ¢Ð Ð¸ ÐÐ¡Ð Ð² ÐÐÐÐÐ. ÐÐ½Ð³Ð¸Ð±Ð¸ÑÐ¾Ð²Ð°Ð½Ð¸Ðµ ÐºÐ¸Ð½Ð°Ð·Ð½Ð¾Ð¹ Ð°ÐºÑÐ¸Ð²Ð½Ð¾ÑÑÐ¸ LRRK2 Ð½Ðµ Ð²Ð»Ð¸ÑÐ»Ð¾ Ð½Ð° Ð°ÐºÑÐ¸Ð²Ð½Ð¾ÑÑÑ GCase Ð¸ ÐºÐ¾Ð½ÑÐµÐ½ÑÑÐ°ÑÐ¸Ñ HexSph Ð² ÐÐÐÐÐ Ð¿Ð°ÑÐ¸ÐµÐ½ÑÐ¾Ð² Ñ ÑÐ¸Ð½ÑÐºÐ»ÐµÐ¸Ð½Ð¾Ð¿Ð°ÑÐ¸ÑÐ¼Ð¸ Ð¸ ÐºÐ¾Ð½ÑÑÐ¾Ð»Ñ. ÐÑÐ»Ð¾ Ð¿Ð¾ÐºÐ°Ð·Ð°Ð½Ð¾, ÑÑÐ¾ Ð¿Ð°ÑÐ¸ÐµÐ½ÑÑ ÑÐ¾ ÑÐÐ ÑÐ°ÑÐ°ÐºÑÐµÑÐ¸Ð·ÑÑÑÑÑ ÑÐ²ÐµÐ»Ð¸ÑÐµÐ½Ð¸ÐµÐ¼ Ð¾ÑÐ½Ð¾ÑÐ¸ÑÐµÐ»ÑÐ½Ð¾Ð³Ð¾ ÑÑÐ¾Ð²Ð½Ñ Ð±ÐµÐ»ÐºÐ° p62. ÐÐ½Ð³Ð¸Ð±Ð¸ÑÐ¾Ð²Ð°Ð½Ð¸Ðµ ÐºÐ¸Ð½Ð°Ð·Ð½Ð¾Ð¹ Ð°ÐºÑÐ¸Ð²Ð½Ð¾ÑÑÐ¸ LRRK2 Ð¿ÑÐ¸Ð²Ð¾Ð´Ð¸Ñ Ðº ÑÐ²ÐµÐ»Ð¸ÑÐµÐ½Ð¸Ñ Ð±ÐµÐ»ÐºÐ° p62 Ð¸ GCase Ð² ÐÐÐÐÐ Ð¿Ð°ÑÐ¸ÐµÐ½ÑÐ¾Ð² ÑÐ¾ ÑÐÐ Ð¿ÑÐ¸ Ð¾ÑÑÑÑÑÑÐ²Ð¸Ð¸ Ð¸Ð·Ð¼ÐµÐ½ÐµÐ½Ð¸Ð¹ Ð² ÑÑÐ¾Ð²Ð½Ðµ LC3-II.
description: This work is devoted to assessing the effect of inhibition of leucine-rich repeat kinase 2 (LRRK2) kinase activity on lysosomal hydrolase activity and the level of protein markers of autophagy in primary culture of peripheral blood macrophages of patients with sporadic Parkinsons disease (sPD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA). A primary culture of peripheral blood macrophages of patients with sPD, DLB, MSA and control was obtained and cultivated in the presence and without the selective inhibitor of LRRK2 kinase activity MLi-2. The effect of LRRK2 kinase activity inhibition on the activity of the lysosomal enzyme glucocerebrosidase (GCase) and the substrate glucosylsphingosine (HexSph) was assessed by high-performance liquid chromatography in combination with tandem mass spectrometry and on the relative level of p62 and LC3-II proteins by Western blotting in the primary culture of macrophages of patients with sPD, DLB, MSA and control. Also, for the first time the effect of LRRK2 kinase activity inhibition on the relative level of GCase in patients with sPD was shown. The efficiency of kinase activity inhibition was confirmed by the effect of MLi-2 on the pT73-Rab10 protein. The study showed a decrease in GCase activity in patients with MSA and an increase in HexSph concentration in patients with sPD, DLB and MSA in the primary culture of peripheral blood macrophages. Inhibition of LRRK2 kinase activity did not affect GCase activity and HexSph concentration in the primary culture of peripheral blood macrophages of patients with synucleinopathies and controls. It was shown that patients with sPD are characterized by an increase in the relative level of p62 protein. Inhibition of LRRK2 kinase activity leads to an increase in p62 and GCase protein in the primary culture of peripheral blood macrophages of patients with sPD in the absence of changes in the LC3-II level.