A proteomic analysis of LRRK2 binding partners reveals interactions with multiple signaling components of the WNT/PCP pathway

Salašová, Alena; Yokota, Chika; Potěšil, David; Zdráhal, Zbyněk; Bryja, Vı́tězslav; Arenas, Ernest

doi:10.1186/s13024-017-0193-9

Cited by 46 publications

(56 citation statements)

References 121 publications

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“…Web-available mass spectrometry data sets have shown that LRRK2 interacts with the paraspeckle proteins NONO and SFPQ (41, 42), suggesting that the LRRK2 protein may also be sequestered in nuclear paraspeckles, in a manner similar to that of other proteins (21). Although LRRK2 mRNA and protein levels did not change significantly in NEAT1-depleted HEK-293T cells (see qPCR and Western blot in Supplemental Fig.…”

Section: Resultsmentioning

confidence: 99%

NEAT1 is overexpressed in Parkinson's disease substantia nigra and confers drug‐inducible neuroprotection from oxidative stress

et al. 2019

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Recent reports attribute numerous regulatory functions to the nuclear paraspeckle‐forming long non‐coding RNA, nuclear enriched assembly transcript 1 (NEAT1), but the implications of its involvement in Parkinson's disease (PD) remain controversial. To address this issue, we assessed NEAT1 expression levels and cell type patterns in the substantia nigra (SN) from 53 donors with and without PD, as well as in interference tissue culture tests followed by multiple in‐house and web‐available models of PD. PCR quantification identified elevated levels of NEAT1 expression in the PD SN compared with control brains, an elevation that was reproducible across a multitude of disease models. In situ RNA hybridization supported neuron‐specific formation of NEATl‐based para‐speckles at the SN and demonstrated coincreases of NEAT1 and paraspeckles in cultured cells under paraquat (PQ)‐induced oxidative stress. Furthermore, neuroprotective agents, including fenofibrate and simvastatin, induced NEAT1 up‐regulation, whereas RNA interference—mediated depletion of NEAT1 exacerbated death of PQ‐exposed cells in a leucine‐rich repeat kinase 2‐mediated manner. Our findings highlight a novel protective role for NEAT1 in PD and suggest a previously unknown mechanism for the neuroprotective traits of widely used preventive therapeutics.—Simchovitz, A., Hanan, M., Niederhoffer, N., Madrer, N., Yayon, N., Bennett, E. R., Greenberg, D. S., Kadener, S., Soreq, H. NEAT1 is overexpressed in Parkinson's disease substantia nigra and confers drug‐inducible neuroprotection from oxidative stress. FASEB J. 33, 11223–11234 (2019). http://www.fasebj.org

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Section: Resultsmentioning

confidence: 99%

NEAT1 is overexpressed in Parkinson's disease substantia nigra and confers drug‐inducible neuroprotection from oxidative stress

et al. 2019

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“…Coimmunoprecipitation (co-IP) assays were carried out as described previously (11,12). Briefly, total protein from HCT116 cells ($5 Â 10 6 /reaction) stably transfected with TTPAL (Flagtagged) expression vector or empty vector was extracted in radioimmunoprecipitation assay (RIPA) buffer supplemented with proteinase inhibitor (Novagen).…”

Section: Coimmunoprecipitation and Liquid Chromatography-mass Spectromentioning

confidence: 99%

TTPAL Promotes Colorectal Tumorigenesis by Stabilizing TRIP6 to Activate Wnt/β-Catenin Signaling

et al. 2019

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Copy number alterations are crucial for the development of colorectal cancer. Our whole-genome analysis identified tocopherol alpha transfer protein-like (TTPAL) as preferentially amplified in colorectal cancer. Here we demonstrate that frequent copy number gain of TTPAL leads to gene overexpression in colorectal cancer from a Chinese cohort (n ¼ 102), which was further validated by a The Cancer Genome Atlas (TCGA) cohort (n ¼ 376). High expression of TTPAL was significantly associated with shortened survival in patients with colorectal cancer. TTPAL promoted cell viability and clonogenicity, accelerated cell-cycle progression, inhibited cell apoptosis, increased cell migration/invasion ability in vitro, and promoted tumorigenicity and cancer metastasis in vivo. TTPAL significantly activated Wnt signaling and increased b-catenin activation and protein expression of cyclin D1 and c-Myc. Coimmunoprecipitation followed by mass spectrometry identified thyroid receptorinteracting protein 6 (TRIP6) as a direct downstream effector of TTPAL. Depletion of TRIP6 significantly abolished the effects of TTPAL on cell proliferation and Wnt activation. Direct binding of TTPAL with TRIP6 in the cytoplasm inhibited ubiquitinmediated degradation of TRIP6 and, subsequently, increased levels of TRIP6 displaced b-catenin from the tumor suppressor MAGI1 via competitive binding. This sequence of events allows b-catenin to enter the nucleus and promotes oncogenic Wnt/ b-catenin signaling. In conclusion, TTPAL is commonly overexpressed in colorectal cancer due to copy number gain, which promotes colorectal tumorigenesis by activating Wnt/b-catenin signaling via stabilization of TRIP6. TTPAL overexpression may serve as an independent new biomarker for the prognosis of patients with colorectal cancer.Significance: TTPAL, a gene preferentially amplified in colorectal cancer, promotes colon tumorigenesis via activation of the Wnt/b-catenin pathway.

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“…Recently, Berwick et al [52] reported that the primary role of LRRK2 in the canonical Wnt signaling pathway is β-catenin repression: loss of LRRK2 increases Wnt/β-catenin activity, whereas overexpressed LRRK2 binds and represses β-catenin. Another study assessing the effect of LRRK2 on Wnt/planar cell polarity (PCP) signaling indicated that LRRK2 activates this pathway via interactions with multiple Wnt/PCP signaling components [53]. These opposing effects suggest that LRRK2 regulates the balance between the Wnt/β-catenin and Wnt/PCP signaling pathways depending on its binding partner.…”

Section: Lrrk2 Mutations and Their Mechanisms Of Actionmentioning

confidence: 99%

Leucine-Rich Repeat Kinase 2 in Parkinson’s Disease: Updated from Pathogenesis to Potential Therapeutic Target

Chen¹,

Chen²,

Pu³

2018

Eur Neurol

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Background: Parkinson’s disease (PD) is characterized by the selective loss of dopaminergic neurons in the midbrain. The pathogenesis of PD is not fully understood but is likely caused by a combination of genetic and environmental factors. Several genes are associated with the onset and progression of familial PD. There is increasing evidence that leucine-rich repeat kinase 2 (LRRK2) plays a significant role in PD pathophysiology. Summary: Many studies have been conducted to elucidate the functions of LRRK2 and identify effective LRRK2 inhibitors for PD treatment. In this review, we discuss the role of LRRK2 in PD and recent progress in the use of LRRK2 inhibitors as therapeutic agents. Key Messages: LRRK2 plays a significant role in the pathophysiology of PD, and pharmacological inhibition of LRRK2 has become one of the most promising potential therapies for PD. Further research is warranted to determine the functions of LRRK2 and expand the applications of LRRK2 inhibitors in PD treatment.

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A proteomic analysis of LRRK2 binding partners reveals interactions with multiple signaling components of the WNT/PCP pathway

Cited by 46 publications

References 121 publications

NEAT1 is overexpressed in Parkinson's disease substantia nigra and confers drug‐inducible neuroprotection from oxidative stress

NEAT1 is overexpressed in Parkinson's disease substantia nigra and confers drug‐inducible neuroprotection from oxidative stress

TTPAL Promotes Colorectal Tumorigenesis by Stabilizing TRIP6 to Activate Wnt/β-Catenin Signaling

Leucine-Rich Repeat Kinase 2 in Parkinson’s Disease: Updated from Pathogenesis to Potential Therapeutic Target

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