Structural Insights and Development of LRRK2 Inhibitors for Parkinson’s Disease in the Last Decade

Thakur, Gunjan; Kumar, Vikas; Lee, Keun Woo; Won, Chung-Kil

doi:10.3390/genes13081426

Cited by 7 publications

(5 citation statements)

References 147 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This observation can be likely explained due to the differences in kinase assays. Type II inhibitors used in this study are less potent than type I inhibitors, as previously reported 15 , 23 , 26 . Additionally, the inhibition assay, with the settings in Supplementary Fig.…”

Section: Resultssupporting

confidence: 52%

Pharmacology of LRRK2 with type I and II kinase inhibitors revealed by cryo-EM

Zhu,

Hixson,

et al. 2024

Cell Discov

View full text Add to dashboard Cite

LRRK2 is one of the most promising drug targets for Parkinson’s disease. Though type I kinase inhibitors of LRRK2 are under clinical trials, alternative strategies like type II inhibitors are being actively pursued due to the potential undesired effects of type I inhibitors. Currently, a robust method for LRRK2–inhibitor structure determination to guide structure-based drug discovery is lacking, and inhibition mechanisms of available compounds are also unclear. Here we present near-atomic-resolution structures of LRRK2 with type I (LRRK2-IN-1 and GNE-7915) and type II (rebastinib, ponatinib, and GZD-824) inhibitors, uncovering the structural basis of LRRK2 inhibition and conformational plasticity of the kinase domain with molecular dynamics (MD) simulations. Type I and II inhibitors bind to LRRK2 in active-like and inactive conformations, so LRRK2–inhibitor complexes further reveal general structural features associated with LRRK2 activation. Our study provides atomic details of LRRK2–inhibitor interactions and a framework for understanding LRRK2 activation and for rational drug design.

show abstract

Section: Resultssupporting

confidence: 52%

Pharmacology of LRRK2 with type I and II kinase inhibitors revealed by cryo-EM

Zhu,

Hixson,

et al. 2024

Cell Discov

View full text Add to dashboard Cite

show abstract

“…Being a kinase, LRRK2 has the ability to phosphorylate multiple proteins depending on its activity and duration of activation [ 71 ]. In its monomeric form, it binds to the 14-3-3 protein in the cytosol, which further acts as a scaffold for numerous signaling proteins and cellular pathways [ 72 ]. With reference to the kinase (G2019S) domain variant of LRRK2, a couple of studies have shown Nrf2-mediated neuroprotection [ 73 , 74 ], but the influence of the mutation on its downstream antioxidants has not been reported.…”

Section: Discussionmentioning

confidence: 99%

Astrocytes Differentiated from LRRK2-I1371V Parkinson’s-Disease-Induced Pluripotent Stem Cells Exhibit Similar Yield but Cell-Intrinsic Dysfunction in Glutamate Uptake and Metabolism, ATP Generation, and Nrf2-Mediated Glutathione Machinery

Banerjee

Raj

Potdar

et al. 2023

Cells

View full text Add to dashboard Cite

Owing to the presence of multiple enzymatic domains, LRRK2 has been associated with a diverse set of cellular functions and signaling pathways. It also has several pathological mutant-variants, and their incidences show ethnicity biases and drug-response differences with expression in dopaminergic-neurons and astrocytes. Here, we aimed to assess the cell-intrinsic effect of the LRRK2-I1371V mutant variant, prevalent in East Asian populations, on astrocyte yield and biology, involving Nrf2-mediated glutathione machinery, glutamate uptake and metabolism, and ATP generation in astrocytes derived from LRRK2-I1371V PD patient iPSCs and independently confirmed in LRRK2-I1371V-overexpressed U87 cells. Astrocyte yield (GFAP-immunopositive) was comparable between LRRK2-I1371V and healthy control (HC) populations; however, the astrocytic capability to mitigate oxidative stress in terms of glutathione content was significantly reduced in the mutant astrocytes, along with a reduction in the gene expression of the enzymes involved in glutathione machinery and nuclear factor erythroid 2-related factor 2 (Nrf2) expression. Simultaneously, a significant decrease in glutamate uptake was observed in LRRK2-I1371V astrocytes, with lower gene expression of glutamate transporters SLC1A2 and SLC1A3. The reduction in the protein expression of SLC1A2 was also directly confirmed. Enzymes catalyzing the generation of γ glutamyl cysteine (precursor of glutathione) from glutamate and the metabolism of glutamate to enter the Krebs cycle (α-ketoglutaric acid) were impaired, with significantly lower ATP generation in LRRK2-I1371V astrocytes. De novo glutamine synthesis via the conversion of glutamate to glutamine was also affected, indicating glutamate metabolism disorder. Our data demonstrate for the first time that the mutation in the LRRK2-I1371V allele causes significant astrocytic dysfunction with respect to Nrf2-mediated antioxidant machinery, AT -generation, and glutamate metabolism, even with comparable astrocyte yields.

show abstract

“…While NEK2 inhibitors have been widely established, and the efficacy was tested in both in vitro and in vivo in several types of cancer, including multiple myeloma, leukemia, gastric, colorectal, glioma, breast, and liver cancers, their effect on lung cancer requires further investigation [ 82 ]. As a key target for Parkinson’s disease, inhibitors for LRRK2 have been developed [ 83 ], but the anticancer effect of this inhibitor has not yet been evaluated. In cancer research, a recent study has demonstrated the role of LRRK2 only in thyroid cancer [ 80 ].…”

Section: Discussionmentioning

confidence: 99%

Evaluating the Expression and Prognostic Value of Genes Encoding Microtubule-Associated Proteins in Lung Cancer

Singharajkomron

Yodsurang

Seephan

et al. 2022

IJMS

View full text Add to dashboard Cite

Microtubule-associated proteins (MAPs) play essential roles in cancer development. This study aimed to identify transcriptomic biomarkers among MAP genes for the diagnosis and prognosis of lung cancer by analyzing differential gene expressions and correlations with tumor progression. Gene expression data of patients with lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) from the Cancer Genome Atlas (TCGA) database were used to identify differentially expressed MAP genes (DEMGs). Their prognostic value was evaluated by Kaplan–Meier and Cox regression analysis. Moreover, the relationships between alterations in lung cancer hallmark genes and the expression levels of DEMGs were investigated. The candidate biomarker genes were validated using three independent datasets from the Gene Expression Omnibus (GEO) database and by quantitative reverse transcription polymerase chain reaction (qRT-PCR) on clinical samples. A total of 88 DEMGs were identified from TCGA data. The 20 that showed the highest differential expression were subjected to association analysis with hallmark genes. Genetic alterations in TP53, EGFR, PTEN, NTRK1, and PIK3CA correlated with the expression of most of these DEMGs. Of these, six candidates—NUF2, KIF4A, KIF18B, DLGAP5, NEK2, and LRRK2—were significantly differentially expressed and correlated with the overall survival (OS) of the patients. The mRNA expression profiles of these candidates were consistently verified using three GEO datasets and qRT-PCR on patient lung tissues. The expression levels of NUF2, KIF4A, KIF18B, DLGAP5, NEK2, and LRRK2 can serve as diagnostic biomarkers for LUAD and LUSC. Moreover, the first five can serve as prognostic biomarkers for LUAD, while LRRK2 can be a prognostic biomarker for LUSC. Our research describes the novel role and potential application of MAP-encoding genes in clinical practice.

show abstract

Structural Insights and Development of LRRK2 Inhibitors for Parkinson’s Disease in the Last Decade

Cited by 7 publications

References 147 publications

Pharmacology of LRRK2 with type I and II kinase inhibitors revealed by cryo-EM

Pharmacology of LRRK2 with type I and II kinase inhibitors revealed by cryo-EM

Astrocytes Differentiated from LRRK2-I1371V Parkinson’s-Disease-Induced Pluripotent Stem Cells Exhibit Similar Yield but Cell-Intrinsic Dysfunction in Glutamate Uptake and Metabolism, ATP Generation, and Nrf2-Mediated Glutathione Machinery

Evaluating the Expression and Prognostic Value of Genes Encoding Microtubule-Associated Proteins in Lung Cancer

Contact Info

Product

Resources

About