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Article: Urinary Biomarkers for Neurodegenerative Diseases.

Seol, Wongi / Kim, Hyejung / Son, Ilhong

2020 Volume 29, Issue 5, Page(s) 325–333

Abstract: Global incidence of neurodegenerative diseases (NDDs) such as Alzheimer's disease (AD) and Parkinson's disease (PD) is rapidly increasing, but the diagnosis of these diseases at their early stage is challenging. Therefore, the availability of ... ...

Abstract	Global incidence of neurodegenerative diseases (NDDs) such as Alzheimer's disease (AD) and Parkinson's disease (PD) is rapidly increasing, but the diagnosis of these diseases at their early stage is challenging. Therefore, the availability of reproducible and reliable biomarkers to diagnose such diseases is more critical than ever. In addition, biomarkers could be used not only to diagnose diseases but also to monitor the development of disease therapeutics. Urine is an excellent biofluid that can be utilized as a source of biomarker to diagnose not only several renal diseases but also other diseases because of its abundance in invasive sampling. However, urine was conventionally regarded as inappropriate as a source of biomarker for neurodegenerative diseases because it is anatomically distant from the central nervous system (CNS), a major pathologic site of NDD, in comparison to other biofluids such as cerebrospinal fluid (CSF) and plasma. However, recent studies have suggested that urine could be utilized as a source of NDD biomarker if an appropriate marker is predetermined by metabolomic and proteomic approaches in urine and other samples. In this review, we summarize such studies related to NDD.
Language	English
Publishing date	2020-11-05
Publishing country	Korea (South)
Document type	Journal Article ; Review
ZDB-ID	2639017-6
ISSN	2093-8144 ; 1226-2560
ISSN (online)	2093-8144
ISSN	1226-2560
DOI	10.5607/en20042
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Article ; Online: LRRK2 Inhibition Mitigates the Neuroinflammation Caused by TLR2-Specific α-Synuclein and Alleviates Neuroinflammation-Derived Dopaminergic Neuronal Loss.

Ho, Dong-Hwan / Nam, Daleum / Seo, Mikyoung / Park, Sung-Woo / Seol, Wongi / Son, Ilhong

Cells

2022 Volume 11, Issue 5

Abstract: Evidence suggests that crosstalk occurs between microglial leucine-rich repeat kinase 2 (LRRK2)-a regulator of neuroinflammation-and neuron-released α-synuclein (αSyn)-a promoter of microglial activation and neuroinflammatory responses-in ... ...

Abstract	Evidence suggests that crosstalk occurs between microglial leucine-rich repeat kinase 2 (LRRK2)-a regulator of neuroinflammation-and neuron-released α-synuclein (αSyn)-a promoter of microglial activation and neuroinflammatory responses-in neuroinflammation-mediated Parkinson's disease (PD) progression. Therefore, we examined whether LRRK2 inhibition reduces the responses of microglia to neuroinflammation caused by neuron-released αSyn. We examined the neuroinflammatory responses provoked by Toll-like receptor 2 (TLR2)-positive αSyn of neuronal cells using an LRRK2 inhibitor in the mouse glioma cells, rat primary microglia, and human microglia cell line; and the effects of LRRK2 inhibitor in the co-culture of ectopic αSyn-expressing human neuroblastoma cells and human microglia cells and in mouse models by injecting αSyn. We analyzed the association between LRRK2 activity and αSyn oligomer and TLR2 levels in the substantia nigra tissues of human patients with idiopathic PD (iPD). The TLR2-specific αSyn elevated LRRK2 activity and neuroinflammation, and the LRRK2 inhibitor ameliorated neuroinflammatory responses in various microglia cells, alleviated neuronal degeneration along with neuroinflammation in the co-culture, and blocked the further progression of locomotor failure and dopaminergic neuronal degeneration caused by TLR2-specific αSyn in mice. Furthermore, LRRK2 phosphorylation was increased in patients with iPD showing αSyn-specific high TLR2 level. These results suggest the application of LRRK2 inhibitors as a novel therapeutic approach against αSyn-mediated PD progression.
MeSH term(s)	Animals ; Dopamine ; Humans ; Inflammation/drug therapy ; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/genetics ; Mice ; Neuroinflammatory Diseases ; Parkinson Disease/drug therapy ; Rats ; Toll-Like Receptor 2 ; alpha-Synuclein
Chemical Substances	TLR2 protein, human ; Tlr2 protein, mouse ; Toll-Like Receptor 2 ; alpha-Synuclein ; LRRK2 protein, human (EC 2.7.11.1) ; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 (EC 2.7.11.1) ; Dopamine (VTD58H1Z2X)
Language	English
Publishing date	2022-03-02
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2661518-6
ISSN	2073-4409 ; 2073-4409
ISSN (online)	2073-4409
ISSN	2073-4409
DOI	10.3390/cells11050861
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Article ; Online: LRRK2 Inhibition Mitigates the Neuroinflammation Caused by TLR2-Specific α-Synuclein and Alleviates Neuroinflammation-Derived Dopaminergic Neuronal Loss

Dong-Hwan Ho / Daleum Nam / Mikyoung Seo / Sung-Woo Park / Wongi Seol / Ilhong Son

Cells, Vol 11, Iss 861, p

2022 Volume 861

Abstract: Evidence suggests that crosstalk occurs between microglial leucine-rich repeat kinase 2 (LRRK2)—a regulator of neuroinflammation—and neuron-released α-synuclein (αSyn)—a promoter of microglial activation and neuroinflammatory responses—in ... ...

Abstract	Evidence suggests that crosstalk occurs between microglial leucine-rich repeat kinase 2 (LRRK2)—a regulator of neuroinflammation—and neuron-released α-synuclein (αSyn)—a promoter of microglial activation and neuroinflammatory responses—in neuroinflammation-mediated Parkinson’s disease (PD) progression. Therefore, we examined whether LRRK2 inhibition reduces the responses of microglia to neuroinflammation caused by neuron-released αSyn. We examined the neuroinflammatory responses provoked by Toll-like receptor 2 (TLR2)-positive αSyn of neuronal cells using an LRRK2 inhibitor in the mouse glioma cells, rat primary microglia, and human microglia cell line; and the effects of LRRK2 inhibitor in the co-culture of ectopic αSyn-expressing human neuroblastoma cells and human microglia cells and in mouse models by injecting αSyn. We analyzed the association between LRRK2 activity and αSyn oligomer and TLR2 levels in the substantia nigra tissues of human patients with idiopathic PD (iPD). The TLR2-specific αSyn elevated LRRK2 activity and neuroinflammation, and the LRRK2 inhibitor ameliorated neuroinflammatory responses in various microglia cells, alleviated neuronal degeneration along with neuroinflammation in the co-culture, and blocked the further progression of locomotor failure and dopaminergic neuronal degeneration caused by TLR2-specific αSyn in mice. Furthermore, LRRK2 phosphorylation was increased in patients with iPD showing αSyn-specific high TLR2 level. These results suggest the application of LRRK2 inhibitors as a novel therapeutic approach against αSyn-mediated PD progression.
Keywords	Parkinson’s disease ; α-synuclein ; leucine-rich repeat kinase 2 (LRRK2) ; neuroinflammation ; Biology (General) ; QH301-705.5
Subject code	616
Language	English
Publishing date	2022-03-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
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Article ; Online: Bi-directional regulation of AIMP2 and its splice variant on PARP-1-dependent neuronal cell death; Therapeutic implication for Parkinson's disease.

Lee, Min Hak / Um, Ki-Hwan / Lee, Seok Won / Sun, Ye Ji / Gu, Da-Hye / Jo, Young Ok / Kim, Sung Hyun / Seol, Wongi / Hwang, Hyorin / Baek, Kyunghwa / Choi, Jin Woo

Acta neuropathologica communications

2024 Volume 12, Issue 1, Page(s) 5

Abstract: Background: Parthanatos represents a critical molecular aspect of Parkinson's disease, wherein AIMP2 aberrantly activates PARP-1 through direct physical interaction. Although AIMP2 ought to be a therapeutic target for the disease, regrettably, it is ... ...

Abstract	Background: Parthanatos represents a critical molecular aspect of Parkinson's disease, wherein AIMP2 aberrantly activates PARP-1 through direct physical interaction. Although AIMP2 ought to be a therapeutic target for the disease, regrettably, it is deemed undruggable due to its non-enzymatic nature and predominant localization within the tRNA synthetase multi-complex. Instead, AIMP2 possesses an antagonistic splice variant, designated DX2, which counteracts AIMP2-induced apoptosis in the p53 or inflammatory pathway. Consequently, we examined whether DX2 competes with AIMP2 for PARP-1 activation and is therapeutically effective in Parkinson's disease. Methods: The binding affinity of AIMP2 and DX2 to PARP-1 was contrasted through immunoprecipitation. The efficacy of DX2 in neuronal cell death was assessed under 6-OHDA and H2O2 in vitro conditions. Additionally, endosomal and exosomal activity of synaptic vesicles was gauged in AIMP2 or DX2 overexpressed hippocampal primary neurons utilizing optical live imaging with VAMP-vGlut1 probes. To ascertain the role of DX2 in vivo, rotenone-induced behavioral alterations were compared between wild-type and DX2 transgenic animals. A DX2-encoding self-complementary adeno-associated virus (scAAV) was intracranially injected into 6-OHDA induced in vivo animal models, and their mobility was examined. Subsequently, the isolated brain tissues were analyzed. Results: DX2 translocates into the nucleus upon ROS stress more rapidly than AIMP2. The binding affinity of DX2 to PARP-1 appeared to be more robust compared to that of AIMP2, resulting in the inhibition of PARP-1 induced neuronal cell death. DX2 transgenic animals exhibited neuroprotective behavior in rotenone-induced neuronal damage conditions. Following a single intracranial injection of AAV-DX2, both behavior and mobility were consistently ameliorated in neurodegenerative animal models induced by 6-OHDA. Conclusion: AIMP2 and DX2 are proposed to engage in bidirectional regulation of parthanatos. They physically interact with PARP-1. Notably, DX2's cell survival properties manifest exclusively in the context of abnormal AIMP2 accumulation, devoid of any tumorigenic effects. This suggests that DX2 could represent a distinctive therapeutic target for addressing Parkinson's disease in patients.
MeSH term(s)	Animals ; Humans ; Poly(ADP-ribose) Polymerase Inhibitors ; Nuclear Proteins/metabolism ; Hydrogen Peroxide ; Oxidopamine ; Parkinson Disease/genetics ; Parkinson Disease/therapy ; Parthanatos ; Rotenone ; Cell Line, Tumor
Chemical Substances	Poly(ADP-ribose) Polymerase Inhibitors ; Nuclear Proteins ; Hydrogen Peroxide (BBX060AN9V) ; Oxidopamine (8HW4YBZ748) ; Rotenone (03L9OT429T) ; AIMP2 protein, human
Language	English
Publishing date	2024-01-03
Publishing country	England
Document type	Journal Article
ZDB-ID	2715589-4
ISSN	2051-5960 ; 2051-5960
ISSN (online)	2051-5960
ISSN	2051-5960
DOI	10.1186/s40478-023-01697-5
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Article: Rab GTPases as Physiological Substrates of LRRK2 Kinase.

Seol, Wongi / Nam, Daleum / Son, Ilhong

Experimental neurobiology

2019 Volume 28, Issue 2, Page(s) 134–145

Abstract: LRRK2 (Leucine-Rich Repeat Kinase 2) is a gene whose specific mutations cause Parkinson's disease (PD), the most common neurodegenerative movement disorder. LRRK2 harbors GTPase and kinase activities, two enzyme activities that play critical roles in the ...

Abstract	LRRK2 (Leucine-Rich Repeat Kinase 2) is a gene whose specific mutations cause Parkinson's disease (PD), the most common neurodegenerative movement disorder. LRRK2 harbors GTPase and kinase activities, two enzyme activities that play critical roles in the regulation of cellular signal transduction. Among the several LRRK2 pathogenic mutations, the most prevalent G2019S mutation increases its kinase activity when compared with the wild-type (WT), suggesting that LRRK2 kinase substrates are potential culprits of PD pathogenesis. Although there were several studies to identify LRRK2 kinase substrates, most of them mainly employed in vitro kinase assays. Therefore, it remains uncertain whether the identified substrates were real physiological substrates. However, efforts to determine physiological LRRK2 kinase substrates have recently identified several members of the Rab GTPase family as physiological LRRK2 kinase substrates. A conserved threonine or serine in the switch II domain of certain Rab GTPase family members (Rab3A/B/C/D, Rab5A/B, Rab8A/B, Rab10, Rab12, Rab29, Rab35 and Rab43) has been pinpointed to be phosphorylated by LRRK2 in cells using sophisticated phosphoproteomics technology in combination with LRRK2-specific kinase inhibitors. The Rab GTPases regulate vesicle trafficking, suggesting that LRRK2 may be a regulator of such vesicle trafficking, confirming previously suggested LRRK2 functions. However, how the consequence of the LRRK2-mediated Rab phosphorylation is related to PD pathogenesis is not clear. This review briefly summarizes the recent results about LRRK2-mediated Rab phosphorylation studies.
Language	English
Publishing date	2019-04-30
Publishing country	Korea (South)
Document type	Journal Article ; Review
ZDB-ID	2639017-6
ISSN	2093-8144 ; 1226-2560
ISSN (online)	2093-8144
ISSN	1226-2560
DOI	10.5607/en.2019.28.2.134
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Article ; Online: Biochemical and molecular features of LRRK2 and its pathophysiological roles in Parkinson's disease.

Seol, Wongi

BMB reports

2010 Volume 43, Issue 4, Page(s) 233–244

Abstract: Parkinson's disease (PD) is the second most common neurodegenerative disease, and 5-10% of the PD cases are genetically inherited as familial PD (FPD). LRRK2 (leucine-rich repeat kinase 2) was first reported in 2004 as a gene corresponding to PARK8, an ... ...

Abstract	Parkinson's disease (PD) is the second most common neurodegenerative disease, and 5-10% of the PD cases are genetically inherited as familial PD (FPD). LRRK2 (leucine-rich repeat kinase 2) was first reported in 2004 as a gene corresponding to PARK8, an autosomal gene whose dominant mutations cause familial PD. LRRK2 contains both active kinase and GTPase domains as well as protein-protein interaction motifs such as LRR (leucine-rich repeat) and WD40. Most pathogenic LRRK2 mutations are located in either the GTPase or kinase domain, implying important roles for the enzymatic activities in PD pathogenic mechanisms. In comparison to other PD causative genes such as parkin and PINK1, LRRK2 exhibits two important features. One is that LRRK2's mutations (especially the G2019S mutation) were observed in sporadic as well as familial PD patients. Another is that, among the various PDcausing genes, pathological characteristics observed in patients carrying LRRK2 mutations are the most similar to patients with sporadic PD. Because of these two observations, LRRK2 has been intensively investigated for its pathogenic mechanism (s) and as a target gene for PD therapeutics. In this review, the general biochemical and molecular features of LRRK2, the recent results of LRRK2 studies and LRRK2's therapeutic potential as a PD target gene will be discussed.
MeSH term(s)	Humans ; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 ; Mutation ; Parkinson Disease/enzymology ; Parkinson Disease/etiology ; Parkinson Disease/genetics ; Protein Structure, Tertiary ; Protein-Serine-Threonine Kinases/chemistry ; Protein-Serine-Threonine Kinases/genetics ; Protein-Serine-Threonine Kinases/metabolism
Chemical Substances	LRRK2 protein, human (EC 2.7.11.1) ; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 (EC 2.7.11.1) ; Protein-Serine-Threonine Kinases (EC 2.7.11.1)
Language	English
Publishing date	2010-03-24
Publishing country	Korea (South)
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2410389-5
ISSN	1976-670X ; 1976-6696
ISSN (online)	1976-670X
ISSN	1976-6696
DOI	10.5483/bmbrep.2010.43.4.233
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Article ; Online: LRRK2 Kinase Inhibitor Rejuvenates Oxidative Stress-Induced Cellular Senescence in Neuronal Cells.

Ho, Dong Hwan / Nam, Daleum / Seo, Mi Kyoung / Park, Sung Woo / Seol, Wongi / Son, Ilhong

Oxidative medicine and cellular longevity

2021 Volume 2021, Page(s) 9969842

Abstract: Background: Leucine-rich repeat kinase 2 (LRRK2) plays a critical role in the pathogenesis of Parkinson's disease (PD). Aging is the most critical risk factor for the progression of PD. The correlation between aging and cellular senescence has been ... ...

Abstract	Background: Leucine-rich repeat kinase 2 (LRRK2) plays a critical role in the pathogenesis of Parkinson's disease (PD). Aging is the most critical risk factor for the progression of PD. The correlation between aging and cellular senescence has been established. Cellular senescence is correlated with the dysregulation of the proteolytic pathway and mitochondrial dysfunction, which are also associated with the aggregation of Methods: Human dopaminergic neuron-like cells (differentiated SH-SY5Y cells) were treated with rotenone in the presence or absence of the LRRK2 kinase inhibitor GSK2578215A (GSK-KI) for 48 h. The markers of cellular senescence, including p53, p21 Results: Rotenone upregulated LRRK2 phosphorylation and Conclusions: Rotenone-induced upregulation of LRRK2 kinase activity promoted cellular senescence, which enhanced
MeSH term(s)	Aging/drug effects ; Aging/physiology ; Cellular Senescence/drug effects ; Cellular Senescence/physiology ; Humans ; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/antagonists & inhibitors ; Lysosomes/drug effects ; Lysosomes/metabolism ; Neurons/drug effects ; Oxidative Stress/drug effects ; Oxidative Stress/physiology ; Parkinson Disease/drug therapy ; Parkinson Disease/metabolism ; Rotenone/pharmacology
Chemical Substances	Rotenone (03L9OT429T) ; LRRK2 protein, human (EC 2.7.11.1) ; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 (EC 2.7.11.1)
Language	English
Publishing date	2021-07-08
Publishing country	United States
Document type	Journal Article
ZDB-ID	2455981-7
ISSN	1942-0994 ; 1942-0994
ISSN (online)	1942-0994
ISSN	1942-0994
DOI	10.1155/2021/9969842
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Article ; Online: Upregulation of the p53-p21 pathway by G2019S LRRK2 contributes to the cellular senescence and accumulation of α-synuclein.

Ho, Dong Hwan / Seol, Wongi / Son, Ilhong

Cell cycle (Georgetown, Tex.)

2019 Volume 18, Issue 4, Page(s) 467–475

Abstract: Parkinson's disease (PD) is characterized by the degeneration of dopaminergic neurons in the substantia nigra and the presence of Lewy bodies (LB) in neurons. α-Synuclein (αSyn) is a major component of LB and promote the PD pathogenesis via its ... ...

Abstract	Parkinson's disease (PD) is characterized by the degeneration of dopaminergic neurons in the substantia nigra and the presence of Lewy bodies (LB) in neurons. α-Synuclein (αSyn) is a major component of LB and promote the PD pathogenesis via its accumulation by the impaired proteasomal or autophagic clearance. Numerous studies have revealed that the reduction of proteasome activity and autophagy is accelerated by cellular senescence. Leucine-rich repeat kinase 2 (LRRK2) contributes to PD progression and its most prevalent mutation, G2019S LRRK2, increases its activity. Our previous report has shown that the G2019S LRRK2 mutant promoted p53-induced p21 expression and neuronal cytotoxicity. The p53-p21 pathway plays a role in cellular senescence. We hypothesized that the loss of dopaminergic neurons by the stimulated p53-p21 pathway via the G2019S LRRK2 mutation might be associated with cellular senescence, thereby promoting the accumulation of αSyn. We confirmed that the ectopic expression of the phosphomimetic p53 mutant, p21, or G2019 in differentiated SH-SY5Y cells increased the following: 1) the expression of β-galactosidase, a marker of cellular senescence, and the activity of senescence-associated β-galactosidase, 2) endogenous αSyn protein level, but not its mRNA level, and 3) αSyn fibril accumulation in dSH-SY5Y via low proteasome and cathepsin D activities. Elevated oligomeric αSyn and the increase in β-galactosidase with induced p21 were observed in brain lysates of G2019S transgenic mice. Our results suggest that cellular senescence is promoted via the p53-p21 pathway due to the G2019S LRRK2 mutation. Eventually, decreased protein degradation by G2019S-mediated senescence could accelerate αSyn aggregate formation.
MeSH term(s)	Animals ; Brain/metabolism ; Cathepsin D/metabolism ; Cell Line, Tumor ; Cellular Senescence ; Cyclin-Dependent Kinase Inhibitor p21/genetics ; Cyclin-Dependent Kinase Inhibitor p21/metabolism ; Dopaminergic Neurons/metabolism ; Humans ; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/genetics ; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/metabolism ; Mice ; Mice, Transgenic ; Mutation ; Neuroblastoma/pathology ; Parkinson Disease/metabolism ; Phosphorylation ; Plasmids/genetics ; Transfection ; Tumor Suppressor Protein p53/genetics ; Tumor Suppressor Protein p53/metabolism ; Up-Regulation ; alpha-Synuclein/metabolism ; beta-Galactosidase/metabolism
Chemical Substances	CDKN1A protein, human ; Cdkn1a protein, mouse ; Cyclin-Dependent Kinase Inhibitor p21 ; TP53 protein, human ; Tumor Suppressor Protein p53 ; alpha-Synuclein ; LRRK2 protein, human (EC 2.7.11.1) ; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 (EC 2.7.11.1) ; beta-Galactosidase (EC 3.2.1.23) ; CTSD protein, human (EC 3.4.23.5) ; Cathepsin D (EC 3.4.23.5)
Language	English
Publishing date	2019-02-06
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2146183-1
ISSN	1551-4005 ; 1538-4101 ; 1554-8627
ISSN (online)	1551-4005
ISSN	1538-4101 ; 1554-8627
DOI	10.1080/15384101.2019.1577666
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Article ; Online: Effect of leucine-rich repeat kinase 2 (LRRK2) on protein synthesis

Hyejung Kim / Ilhong Son / Wongi Seol

Animal Cells and Systems, Vol 22, Iss 1, Pp 15-

2018 Volume 21

Abstract: Mutations in the leucine-rich repeat kinase 2 (LRRK2) cause Parkinson’s disease (PD) in an autosomal dominant manner. Pathogenic mutations of LRRK2 such as G2019S and R1441C have been observed as common genetic causes of PD. Recently, LRRK2 has been ... ...

Abstract	Mutations in the leucine-rich repeat kinase 2 (LRRK2) cause Parkinson’s disease (PD) in an autosomal dominant manner. Pathogenic mutations of LRRK2 such as G2019S and R1441C have been observed as common genetic causes of PD. Recently, LRRK2 has been reported to increase the reporter protein synthesis in both cap-dependent and -independent manners via phosphorylation of the ribosomal protein RPS15. In this study, we tested whether LRRK2 recombinant protein would directly increase protein synthesis using a well-defined in vitro coupled transcription/translation system. Addition of commercial full-length LRRK2 or GST-fused N-terminal-deleted LRRK2 recombinant proteins to the system showed no change of protein synthesis, as measured by luciferase reporter activity. In addition, the SUnSET assay to measure newly synthesized cellular proteins showed that G2019S overexpression had a minimal effect on the total protein amount. However, we confirmed the previous result that G2019S overexpression increased the amount of protein synthesized from an exogenous gene, Flag-VAMP2, which was transfected as a reporter, whereas there was no significant change in the amount of the Flag-VAMP2 mRNA. Inhibition of protein degradation showed that protein accumulation in the vector control was higher than that of the G2019S overexpression vector. Our results suggest that LRRK2 protein influences the amount of protein by inhibiting protein degradation rather than by directly stimulating translation.
Keywords	Protein synthesis ; LRRK2 ; Parkinson’s disease ; G2019S ; kinase ; Medicine (General) ; R5-920 ; Biology (General) ; QH301-705.5
Subject code	570
Language	English
Publishing date	2018-01-01T00:00:00Z
Publisher	Taylor & Francis Group
Document type	Article ; Online
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Article: G2019s LRRK2 promotes mitochondrial fission and increases TNFα-mediated neuroinflammation responses.

Ho, Dong Hwan / Lee, Heajin / Son, Ilhong / Seol, Wongi

Animal cells and systems

2019 Volume 23, Issue 2, Page(s) 106–111

Abstract: Leucine rich-repeat kinase 2 (LRRK2) is involved in the pathogenesis of Parkinson's disease (PD). LRRK2 has kinase and GTPase activities, and mediates several cell functions, including vesicle trafficking, apoptosis, autophagy, mitochondrial dynamics, ... ...

Abstract	Leucine rich-repeat kinase 2 (LRRK2) is involved in the pathogenesis of Parkinson's disease (PD). LRRK2 has kinase and GTPase activities, and mediates several cell functions, including vesicle trafficking, apoptosis, autophagy, mitochondrial dynamics, and neuroinflammation. G2019S (GS) is the most prevalent mutation of LRRK2. The mutation increases kinase activity, suggesting that this activity is crucial for PD pathogenesis. The activation and inhibition of LRRK2 kinase increases and reduces the levels of proinflammatory cytokines, respectively suggesting that the role of LRRK2 in neuroinflammation is critical for the pathology of PD. Previously, we demonstrated that microglial activation by lipopolysaccharide (LPS) increases mitochondrial fission via the activation of LRRK2 kinase, while LRRK2 kinase inhibition diminishes the fission morphology and release of tumor necrosis factor-alpha (TNFα) in BV2 or rat primary microglia and the brains of GS transgenic mice. In this study, the ectopic expression of GS LRRK2 in BV2 cells significantly elevated the expression of Drp1 along the fragmented mitochondria and decreased mitochondria size compared with controls. GS LRRK2-transfected BV2 cells displayed significantly increased TNFα release and neuronal death. Inhibition of LRRK2 kinase alleviated these features. TNFα levels in brains of GS mice were significantly increased compared to those in their littermates. These data further support our previous findings concerning LPS-induced neuroinflammation and mitochondrial fission in microglia via LRRK2 kinase activation.
Language	English
Publishing date	2019-03-01
Publishing country	England
Document type	Journal Article
ZDB-ID	2562988-8
ISSN	2151-2485 ; 1976-8354
ISSN (online)	2151-2485
ISSN	1976-8354
DOI	10.1080/19768354.2019.1585948
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