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Polyubiquitin-Proteasomal Degradation of Leucine-Rich Repeat Kinase 2 Wildtype and G2019S
Biomed Sci Letters 2021;27:182-186
Published online September 30, 2021;  https://doi.org/10.15616/BSL.2021.27.3.182
© 2021 The Korean Society For Biomedical Laboratory Sciences.

Sangwook Park†,*

Department of Biomedical Laboratory Science, College of Health and Medical Science, Sangji University, Wonju 26339, Korea
Correspondence to: Sangwook Park. Department of Biomedical Laboratory Science, College of Health and Medical Science, Sangji University, 83 Sangjidae-gil, Wonju-si, Gangwon-do 26339, Korea.
Tel: +82-33-738-7682, Fax: +82-33-738-7652, e-mail: spark367@sangji.ac.kr
*Professor.
Received July 19, 2021; Revised August 6, 2021; Accepted August 10, 2021.
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
 Abstract
Parkinson disease (PD) is becoming one of the most neurodegenerative disorder worldwide. The deposited aggregates have been connected in the pathophysiology of PD, which are degraded either by ubiquitin-proteasomal system (UPS) or autophagy-lysosomal pathway (ALP). Leucin-rich repeat kinase 2 (LRRK2), one of the neurodegenerative proteins of PD is also stringently controlled by both UPS and ALP degradation as well. However, the polyubiquitination pattern of LRRK2 aggregates is largely unknown. Here, we found that K63-linked polyubiquitinations of G2019S mutant, most familial variant for PD, is highly enhanced compared to those of wild type LRRK2 (WT). In addition, in the presence of overexpressed p62/SQSTM-1, ubiquitination of LRRK2 WT or D1994A was reduced, whereas G2019S mutant was not diminished significantly. Therefore, we propose that degradation of G2019S via UPS is more involved with K63-linked ubiquitination than K48-linked ubiquitination, and overexpressed p62/SQSTM-1 does not enhance degradative effect on G2019S variant.
Keywords : Leucin-rich repeat kinase 2, Parkinson disease, P62/SQSTM-1, Ubiquitin-Proteasomal system
Body

뙆궓뒯蹂(Parkinson disease, PD) 蹂묐━븰쟻쑝濡 以묐뇤쓽 쓳깋吏(substantia nigra) 遺쐞뿉 룄뙆誘쇱꽦 돱윴씠 냼떎릺뼱 씪뼱굹뒗 吏덈퀝쑝濡 옒 븣젮졇 엳쑝硫 α-synuclein 쓳吏(aggregate)쓣 굹궡뒗 꽭룷꽦 遊됱엯泥(inclusion)씤 Lewy body瑜 삎꽦븳떎. 臾쇰줎 엫긽쟻쑝濡 뙆궎뒯蹂 솚옄媛 媛吏怨 엳뒗 슫룞꽦 利앹긽뱾-넀뼥由, 洹쇱쑁쓽 寃쎌쭅꽦, 뒓由고뻾룞 벑怨 鍮꾩슫룞꽦 利앹긽-蹂鍮, 썑媛곸긽떎, 슦슱利, 닔硫댁옣븷 벑씠 鍮꾨룄뙆誘쇱꽦 떊寃쎌꽭룷 뿰愿릺뼱 엳떎(Simon et al., 2020). PD瑜 쑀諛쒖떆궎뒗 쑀쟾옄뒗 α-synuclein쓣 삎꽦븯뒗 SNCA (Polymeropoulos et al., 1997), PARKIN (Valente et al., 2004)怨 PINK1 (Shin et al., 2011) 벑 mitophagy瑜 쑀룄븯怨, 쟾궗씤옄씤 NRF2瑜 넻빐 빆궛솕슚怨쇰 쑀룄븯뒗 DJ-1 (Bonifati et al., 2003), Gaucher's disease 뿰愿맂 GBA (β-glucocerebrosidase) 쑀쟾옄(Clark et al., 2005), 洹몃━怨 媛議깆꽦 PD쓽 5%, 쟾泥 PD 솚옄쓽 ~2% 媛웾쓣 李⑥븯뒗 LRRK2 (Alessi and Sammler, 2018) 벑씠 엳떎. Leucine-rich repeat kinase 2 (LRRK2)뒗 GTPase kinase 룄硫붿씤 벑쓣 븿쑀븯뒗 2,527媛 븘誘몃끂궛쑝濡 援ъ꽦맂 286 kDa쓽 遺꾩옄웾쓣 吏땶 留ㅼ슦 겙 떒諛깆쭏씠떎(Cookson, 2010). LRRK2 쑀쟾옄쓽 떎뼇븳 룎뿰蹂씠뱾씠 뙆궓뒯蹂묒쓽 썝씤쑝濡 븣젮졇 엳뒗뜲 G2019S 蹂씠媛 媛옣 쓷엳 諛쒓껄릺硫 씠 룎뿰蹂씠濡 씤빐 kinase 솢꽦쓣 利앷떆궎뒗 寃껋쑝濡 븣젮졇 엳떎(Nguyen et al., 2020). 2013뀈 Orenstein 벑 chaperone-mediated autophagy (CMA)瑜 留ㅺ컻濡 LRRK2媛 lysosome뿉꽌 遺꾪빐맂떎怨 諛앺삍떎(Orenstein, et al., 2013). 理쒓렐뿉 Park 벑 p62/SQSTM-1쓣 留ㅺ컻濡 LRRK2媛 autophagy-lysosomal pathway (ALP)瑜 넻빐 遺꾪빐맂떎怨 蹂닿퀬븯뒗 벑 LRRK2 떒諛깆쭏 궗硫 湲곗쟾뿉 븳 떎뼇븳 寃곌낵媛 蹂닿퀬릺뿀떎(Ho et al., 2020; Park et al., 2016). 吏꾪빑꽭룷뿉꽌 젙긽쟻씤 떒諛깆쭏 냼硫몄 ubiquitin-proteasome system (UPS) ALP瑜 넻빐 꽭룷 궡 떒諛깆쭏 遺꾪빐媛 씠猷⑥뼱吏꾨떎. 理쒓렐 뿰援ъ뿉 쓽븯硫 p62, NBR1 (neighbor of BRCA1 gene 1) (Kirkin et al., 2009), NDP52 (nuclear dot protein 52) (Thurston et al., 2009), OPTN (optineurin) (Liu et al., 2014) 벑씠 꽑깮쟻 옄媛룷떇(autophagy)쓣 넻빐 떒諛깆쭏쓣 냼硫몄떆궎뒗 뿭븷쓣 븳떎. 蹂 뿰援ъ뿉꽌뒗 LRRK2媛 UPS瑜 넻빐 떒諛깆쭏 냼硫몄쓣 愿李고븯떎. 듅엳, G2019S 룎뿰蹂씠 wildtype (LRRK2)媛꾩쓽 ubiquitination 뙣꽩(K48-/K63-linked)쓽 李⑥씠젏쓣 솗씤븯怨 p62쓽 怨쇰컻쁽 떆 polyubiquitination쓽 蹂솕瑜 愿李고븯떎. 씠瑜 넻빐 LRRK2 G2019S쓽 떒諛깆쭏 궗硫멸낵젙쓣 씠빐븯뒗 뜲 룄쓣 以 닔 엳쓣 寃껋쑝濡 湲곕븳떎. LRRK2 wildtype怨 LRRK2 G2019S쓽 polyubiquitination 李⑥씠瑜 솗씤븯湲 쐞븯뿬 怨듬룞硫댁뿭移④컯踰(Co-immunoprecipitation assay, Co-IP)瑜 씠슜븯떎. Myc-LRRK2 HA-Ub (K48) 삉뒗 HA-Ub (K63)瑜 HEK293T 꽭룷뿉 怨듬룞 怨쇰컻쁽 떆궓 썑 anti-Myc antibody瑜 씠슜븯뿬 pull-down 떆궓 썑 anti-HA antibody濡 immunoblot 떆耳 polyubiquitination 뙣꽩쓣 솗씤븯떎. HEK293T 꽭룷瑜 諛곗뼇븯湲 쐞빐 6-well plate뿉 DMEM [10% FBS, Penicillin-Streptomycin (100 U/mL)]쓣 well떦 0.8×106媛쒖뵫 媛곴컖 遺꾩<븯떎. 37℃ 諛곗뼇湲곗뿉 5% CO2 怨듦툒 븯뿉 꽭룷瑜 븞젙쟻쑝濡 諛곗뼇븳 썑, 70~80% 꽭룷媛 옄씪궗쓣 븣 1.5 mL tube뿉 DMEM (serum 誘명룷븿)쓣 30 μL뵫 遺꾩<븯怨 媛 tube뿉 Co-IP뿉 븘슂븳 珥 plasmid 뼇怨 PolyJet (SignaGen Laboratories, USA)쓣 1:3 鍮꾩쑉濡 泥④븯떎. 誘멸怨듬맂(crude) 떒諛깆쭏씤 珥앹꽭룷슜빐臾(total cell lysate)쓣 쉶닔븯湲 쟾 PBS濡 1쉶 꽭泥 썑 ice 쐞뿉 넃怨 protease inhibitor cocktails (Roche, Germany)瑜 珥앹슜웾쓽 1/10 媛웾 泥④븳 RIPA cell lysis buffer (150 mM NaCl, 1% NP-40, 1% sodium deoxycholate, 0.1% SDS, 2 mM EDTA, 50 mM Tris-HCl, pH 7.6)瑜 well떦 200 μL 遺꾩<븳 뮘 cell lifter (SPL, Korea)瑜 씠슜븯뿬 1.5 mL tube뿉 떞븯떎. 쉶닔븳 꽭룷슜빐臾쇱 썝떖遺꾨━(10,000 g, 4℃, 5 min)븯뿬 긽痢듭븸쓣 깉 tube뿉 遺꾨━븳 썑 떎쓬 떎뿕뿉 궗슜븯湲 쟾源뚯 ice뿉 苑귥븘 몢뿀떎. 珥앹꽭룷슜빐臾 긽痢듭븸 200 μL Protein G Sepharose 4 Fast Flow (GE Helthcare, USA) 20 μL瑜 4℃뿉꽌 誘몃━ 젣嫄곗떆耳곕떎(pre-clearing). 썝떖遺꾨━븯뿬 긽痢듭븸쓣 遺꾨━븳 썑 1李 빆泥 1 μL Myc 9E10 (#M5546) (Sigma-Aldrich, USA)瑜 泥④븯뿬 rotary mixer뿉꽌 쉶쟾떆耳 諛섏쓳떆궓 썑(4℃, 1 hr), Protein G Sepharose bead 20 μL瑜 4℃뿉꽌 빟 2떆媛 룞븞 硫댁뿭移④컯(precipitation) 떆耳곕떎. 諛섏쓳 썑 썝떖遺꾨━븯뿬 硫댁뿭移④컯臾쇱쓣 쉶닔븯뿬 lysis buffer濡 3쉶 씠긽 꽭泥 썑 5X sample buffer (60 mM Tris-HCl pH 6.8, 25% glycerol, 2% SDS, 0.1% bromophenol blue, 2% β-mercaptoethanol) 8 μL lysis buffer 32 μL 泥④븯뿬 100℃뿉꽌 5遺꾧컙 걪떎. 1000g 1遺꾧컙 썝떖遺꾨━ 썑 긽痢듭븸쓣 쉶닔븯뿬 SDS-PAGE 쟾湲곗쁺룞 썑 Immunoblot쑝濡 polyubiquitination맂 떒諛깆쭏쓣 遺꾩꽍븯떎. Wildtype (Myc-LRRK2), D1994A (Myc-D1994A, kinase dead variant), G2019S (Myc-G2019S varinat) HA-Ub (K48) 諛 HA-Ub (K63)瑜 HEK293T뿉 怨쇰컻쁽쓣 쑀룄븯떎. 씠썑, 怨듬룞硫댁뿭移④컯踰(Co-Immunoprecipitation assay, Co-IP)쓣 씠슜븯뿬 UPS瑜 넻븳 wildtype LRRK2 mutant 媛꾩쓽 K48- 삉뒗 K63-linked polyubiquitination 솗씤븯떎. Wildtype LRRK2 쑀鍮꾪댄떞솕쓽 寃쎌슦 K48/K63-linked polyubiquitination뿉 李⑥씠瑜 蹂댁씠吏뒗 븡븯떎. 洹몃윭굹 G2019S mutant쓽 寃쎌슦뿉뒗 K63-linked polyubiquitination (Ub)씠 K48-linked Ub 蹂대떎 留롮씠 씪뼱굹뒗 寃쏀뼢쓣 蹂댁떎(P < 0.05). 씤쐞쟻쑝濡 LRRK2쓽 kinase domain 湲곕뒫쓣 鍮꾪솢꽦솕떆궓 D1994A mutant씤 寃쎌슦룄 K63-linked Ub씠 遺遺 씪뼱굹뒗 寃쏀뼢쓣 쓣뿀떎(Fig. 1A, B). 븳렪, p62/SQSTM-1쓣 怨쇰컻쁽(FLAG-p62) 떆궓 썑 wildtype, D1994A, G2019S쓽 Ub怨 endogenous p62 긽깭쓽 LRRK2 (wildtype, D1994A, G2019S)媛꾩쓽 Ub쓣 솗씤븯떎. Wildtype怨 D1994A뒗 怨쇰컻쁽맂 FLAG-p62 議곌굔뿉꽌뒗 삁긽뻽벏씠 autophage lysosomal pathway (ALP)濡 떒諛깆쭏 遺꾪빐寃쏀뼢쓣 蹂댁뿬二쇱뿀떎. 긽쟻쑝濡 쟻 p62瑜 吏냽쟻쑝濡 諛쒗쁽븯뒗 endogenous p62뿉꽌뒗 UPS 寃쎈줈쓽 뿭븷씠 넂 寃껋쑝濡 굹궗떎(P < 0.05). 洹몃윴뜲, G2019S씤 寃쎌슦뿉뒗 p62쓽 쁺뼢쓣 긽쟻쑝濡 쟻寃 諛쏆븯쓬쓣 븣 닔 엳떎(Fig. 1C, D). G2019S variant씤 寃쎌슦뿉뒗 怨쇰컻쁽맂 p62 긽깭뿉꽌룄 긽쟻쑝濡 wildtype怨 鍮꾧탳뻽쓣 븣, ALP 寃쎈줈쓽 쑀鍮꾪댄떞솕瑜 蹂댁뿬二쇱뿀떎. Kinase 룄硫붿씤쓣 鍮꾪솢꽦솕떆궓 D1994A mutant쓽 寃쎌슦, UPS瑜 넻븳 LRRK2쓽 K63-linked Ub씠 G2019S蹂대떎 넂븯떎뒗 젏 씎誘몃∼떎. G2019S쓽 寃쎌슦 kinase 솢꽦씠 利앷뻽뒗 뜲 kinase瑜 뾾븷硫 뜑슧 UPS 寃쎈줈쓽 떒諛깆쭏 遺꾪빐媛 利앷븯뒗 諛, 븘留덈룄 kinase쓽 솢꽦룄媛 UPS 떒諛깆쭏 궗硫몄뿉룄 쁺뼢쓣 以 닔 엳쓣 寃껋쑝濡 蹂몃떎. 蹂 떎뿕 LRRK2媛 UPS 寃쎈줈瑜 넻빐 떒諛깆쭏씠 냼떎맆 븣 K48-linked Ub 삉뒗 K63-linked Ub 寃쎈줈씤吏 솗씤븯떎. 吏꾪빑꽭룷 궡 떒諛깆쭏쓽 냼硫몄 몴쟻씤 寃쎈줈씤 UPS ALP 넻빐 議곗젅맂떎. ALP쓽 泥 떒怨꾩씤 autophagy뒗 mitophagy泥섎읆 phagophore瑜 삎꽦븯뿬 autophagosome쓣 삎꽦븳 썑 lysosome怨 쑖빀븯뿬 autolysosome쓣 삎꽦븯뿬 떒諛깆쭏쓣 빐泥댄븯뒗 삎깭쓽 macroautophagy autophagy쓽 怨쇱젙뾾씠 lysosome/late endosome씠 吏곸젒 궡옱솕븯뿬 遺꾪빐븯뒗 microautophagy, 洹몃━怨 Heat shock cognate 70 (Hsc70)怨 cochaperones씠 遺꾪빐븷 떒諛깆쭏쓣 lysosome쓽 Lamp-2A쓽 솢꽦쓣 쑀룄븿쑝濡쒖뜥 궡옱솕븯뿬 빐泥댄븯뒗 諛⑹떇씤 chaperone-mediated autophagy (CMA)쑝濡 굹닃 닔 엳떎(Mizushima and Komatsu, 2011). 洹 쇅 ER-associated proteasomal degradation (ERAD) 諛⑹떇쓽 떒諛깆쭏 빐泥 寃쎈줈룄 엳떎(Hampton, 2002). LRRK2뒗 primary neurons뿉꽌 proteosome怨 lysosome뿉꽌 떒諛깆쭏 빐泥닿 씠猷⑥뼱吏먯쓣 솗씤븯怨 듅엳 p62 寃고빀븯뿬 꽑깮쟻 옄媛룷떇(autophagy)瑜 넻빐 LRRK2媛 냼硫몃맂떎뒗 궗떎 諛앺議뚮떎(Park et al., 2016). 洹몃윭굹 Orenstein 벑 CMA瑜 넻빐꽌留 LRRK2媛 냼硫몃맂떎怨 蹂닿퀬븯떎. 蹂 뿰援ш껐怨쇰뒗 LRRK2媛 UPS瑜 넻븳 떒諛깆쭏 냼硫몄쓣 吏곸젒 솗씤븯쑝硫 씠뒗 ALP 寃쎈줈肉먮쭔 븘땲씪 UPS 寃쎈줈룄 떒諛깆쭏 냼硫멸낵젙뿉 以묒슂븿쓣 솗씤븷 닔 엳뿀떎. 뼢썑, UPS瑜 넻븳 LRRK2쓽 떒諛깆쭏 냼떎怨쇱젙뿉 愿뿬븯뒗 떒諛깆쭏怨 긽샇愿怨꾨 諛앺 궦떎硫 PD 蹂묒씤꽦쓣 씠빐븯뒗 뜲 룄씠 맆 寃껋쑝濡 湲곕븳떎.

Fig. 1. The ubiquitination of LRRK2 wildtype and G2019S mutant are differentially regulated by p62/SQSTM1. (A) K63-linked ubiquitination is increased in LRRK2 G2019S mutant compared with LRRK2 WT. Myc-tagged LRRK2 WT or G2019S was co-transfected with HA-tagged K48 Ub or K63 Ub in HEK 293T cells. The ubiquitination of LRRK2 was detected using anti-HA antibody following immunoprecipitation with anti-myc antibody. (B) Quantification graph from panel A. The data represent means of ubiquitinated LRRK2 ± SEM (K48-Ub WT, 1.00±0.00; D1994A, 2.67±0.98; G2019S, 1.85±0.93; K63-Ub WT, 1.00±0.00; D1994A, 5.07±1.30; G2019S, 2.81±0.29; n = 3; *P < 0.05, paired t-test). (C) The overexpression of p62 reduces the ubiquitination of LRRK2 WT or D1994A, whereas does not have a significant effect on LRRK2 G2019S mutant. HEK 293T cells were co-transfected with HA-Ub and myc-LRRK2 WT or G2019S, and then the ubiquitination of LRRK2 was detected as in panel A. (D) The summary quantification are shown as means ± SEM (WT, 1.00±0.00; WT with p62, 0.48±0.18; D1994A, 0.69±0.06; D1994A with p62, 0.33±0.09; G2019S, 1.61±0.87; G2019S with p62, 0.60±0.32; n = 3; *P < 0.05, n.s., P > 0.05, paired t-test).
ACKNOWLEDGEMENT

This study was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) grant (http://ernd.nrf.re.kr) to S.P (NRF-2017R1D1A3B03029902), which was funded by the Ministry of Education.

CONFLICT OF INTEREST

The author declares no conflict of interest.

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