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Cited by 252Parkinson's Disease Mechanisms and TreatmentsNuclear Receptors and SignalingDeep Brain Stimulation and Movement Disorders

The DOI matches its Crossref record; 127 of the 127 references it cites were found in a registry or an index.

The role of the LRRK2 gene in Parkinsonism

Open access
Li, Jie-Qiong, Tan, Lan, Yu, Jin-Tai·2014·Molecular Neurodegeneration
DOI 10.1186/1750-1326-9-47PMC PMC4246469
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Abstract

Parkinson's disease (PD), like many common age-related conditions, has been recognized to have a substantial genetic component. Multiple lines of evidence suggest that Leucine-rich repeat kinase 2 (LRRK2) is a crucial factor to understanding the etiology of PD. LRRK2 is a large, widely expressed, multi-domain and multifunctional protein. LRRK2 mutations are the major cause to inherited and sporadic PD. In this review, we discuss the pathology and clinical features which show diversity and variability of LRRK2-associated PD. In addition, we do a thorough literature review and provide theoretical data for gene counseling. Further, we present the evidence linking LRRK2 to various possible pathogenic mechanism of PD such as α-synuclein, tau, inflammatory response, oxidative stress, mitochondrial dysfunction, synaptic dysfunction as well as autophagy-lysosomal system. Based on the above work, we investigate activities both within GTPase and outside enzymatic regions in order to obtain a potential therapeutic approach to solve the LRRK2 problem.

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Crossref · 10.1186/1750-1326-9-47

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Figure 1 Schematic representation of LRRK2 and the pathogenic mutations associated with PD ARM, Armadillo; ANK, Ankyrin repeat; LRR, leucine-rich repeat; ROC, Ras of complex proteins: GTPase; COR, C-terminal of ROC; WD40, WD-40 domain. Potential pathogenic mutations are shown together.
Figure 1 Schematic representation of LRRK2 and the pathogenic mutations associated with PD ARM, Armadillo; ANK, Ankyrin repeat; LRR, leucine-rich repeat; ROC, Ras of complex proteins: GTPase; COR, C-terminal of ROC; WD40, WD-40 domain. Potential pathogenic mutations are shown together.CC BY · PubMed Central
Figure 2 LRRK2-mediated the phosphorylation of tubulin-associated tau LRRK2 interacts with tubulin-associated tau, resulting in the formation of a tripartite complex. The interaction between LRRK2 and β-tubulin is mediated by the LRRK2 Roc domain and β-tubulin C termini. Tubulin-associated tau was phosphorylated by LRRK2. LRRK2 interacted directly with GSK-3β, and that His–GSK-3β bound to the kinase domain of LRRK2 (thick line). Phosphorylation of tau by GSK-3β was stimulated by LRRK2 (thin arrow). P.G2019S-LRRK2 had higher binding affinity for GSK-3β and showed much stronger stimulatory activity (thick line and arrow).
Figure 2 LRRK2-mediated the phosphorylation of tubulin-associated tau LRRK2 interacts with tubulin-associated tau, resulting in the formation of a tripartite complex. The interaction between LRRK2 and β-tubulin is mediated by the LRRK2 Roc domain and β-tubulin C termini. Tubulin-associated tau was phosphorylated by LRRK2. LRRK2 interacted directly with GSK-3β, and that His–GSK-3β bound to the kinase domain of LRRK2 (thick line). Phosphorylation of tau by GSK-3β was stimulated by LRRK2 (thin arrow). P.G2019S-LRRK2 had higher binding affinity for GSK-3β and showed much stronger stimulatory activity (thick line and arrow).CC BY · PubMed Central
Figure 3 The possible pathogenic mechanism links LRRK2 and Parkinson’s disease α-synuclein, tau, inflammatory response, oxidative stress, mitochondrial dysfunction, synaptic dysfunction and autophagy-lysosomal system all take part in the pathogenic of PD. Open and filled arrows show positive (activating) and negative (suppressing) interactions, respectively.
Figure 3 The possible pathogenic mechanism links LRRK2 and Parkinson’s disease α-synuclein, tau, inflammatory response, oxidative stress, mitochondrial dysfunction, synaptic dysfunction and autophagy-lysosomal system all take part in the pathogenic of PD. Open and filled arrows show positive (activating) and negative (suppressing) interactions, respectively.CC BY · PubMed Central

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Metadata

Authors
Li, J.-Q., Tan, L., & Yu, J.-T.
Affiliations
Qingdao University (CN)
Corresponding author
  • Tan, Lan
  • Yu, Jin-Tai
ORCID
Venue
Molecular Neurodegeneration
Publisher
Springer Science and Business Media LLC
Published
2014-11-12
Volume
9
Issue
1
Pages
47-47
ISSN
1750-1326 (ISSN-L)
DOI
10.1186/1750-1326-9-47
PMC
PMC4246469
OpenAlex
W2145005920
Cited by
249
References
127
Citations by year
2026: 9 · 2025: 18 · 2024: 24 · 2023: 29 · 2022: 27 · 2021: 15 · 2020: 28 · 2019: 30 · 2018: 30 · 2017: 17 · 2016: 12 · 2015: 10
FWCI
1.79
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Molecular Neurodegeneration (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • National Natural Science Foundation of China (81371406, ZR2011HZ001, 81171209, 81471309, ZR2010HQ004)
  • Natural Science Foundation of Shandong Province (ZR2011HZ001, ZR2010HQ004)
Topics
  • Health Sciences › Medicine › Clinical Neurology › Parkinson's Disease Mechanisms and Treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Receptors and Signaling
  • Health Sciences › Medicine › Clinical Neurology › Deep Brain Stimulation and Movement Disorders
Keywords
LRRK2, Parkinson's disease, leucine-rich repeat kinase 2, LRRK2 mutations, alpha-synuclein, tau protein, neuroinflammation, oxidative stress, mitochondrial dysfunction, synaptic dysfunction, autophagy-lysosome pathway, therapeutic target
MeSH terms
Leucine-Rich Repeat Serine-Threonine Protein Kinase-2, Animals, Humans, Protein Serine-Threonine Kinases, Parkinsonian Disorders

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