Brain injury induces HIF-1α-dependent transcriptional activation of LRRK2 that exacerbates brain damage

Bae, Yun Jung; Joo, Hyejin; Bae, Jong‐Sup; Hyeon, Seung Jae; Her, Song; Ko, Eunhwa; Choi, Hwan Geun; Ryu, Hoon; Hur, Eun Mi; Bu, Youngmin; Lee, Yong Kyu

doi:10.1038/s41419-018-1180-y

Cited by 44 publications

(42 citation statements)

References 62 publications

(67 reference statements)

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“…More recently, LRRK2 expression was found to increase in CCI mouse TBI model, and LRRK2 inhibition was found to be neuroprotective [5]. Bae et al (2018), show that inhibition of LRRK2 provides robust neuroprotection after a CCI in the cortex and hippocampus and that this neuroprotection results in improved motor function (beam balance) and memory (novel object recognition) tests.…”

Section: Controlled Cortical Impact (Cci) Tbimentioning

confidence: 98%

“…Studies show that gain of function mutations in LRRK2 increase susceptibility to α-syn pathology and that LRRK2 inhibition or knockout provides neuroprotection in multiple PD models [31,86,156]. More recently, LRRK2 expression was found to increase in CCI mouse TBI model, and LRRK2 inhibition was found to be neuroprotective [5]. Bae et al (2018), show that inhibition of LRRK2 provides robust neuroprotection after a CCI in the cortex and hippocampus and that this neuroprotection results in improved motor function (beam balance) and memory (novel object recognition) tests.…”

Section: Controlled Cortical Impact (Cci) Tbimentioning

confidence: 99%

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Biological links between traumatic brain injury and Parkinson’s disease

Delic

Beck

Pang

et al. 2020

acta neuropathol commun

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Parkinson's Disease (PD) is a progressive neurodegenerative disorder with no cure. Clinical presentation is characterized by postural instability, resting tremors, and gait problems that result from progressive loss of A9 dopaminergic neurons in the substantia nigra pars compacta. Traumatic brain injury (TBI) has been implicated as a risk factor for several neurodegenerative diseases, but the strongest evidence is linked to development of PD. Mild TBI (mTBI), is the most common and is defined by minimal, if any, loss of consciousness and the absence of significant observable damage to the brain tissue. mTBI is responsible for a 56% higher risk of developing PD in U.S. Veterans and the risk increases with severity of injury. While the mounting evidence from human studies suggests a link between TBI and PD, fundamental questions as to whether TBI nucleates PD pathology or accelerates PD pathology in vulnerable populations remains unanswered. Several promising lines of research point to inflammation, metabolic dysregulation, and protein accumulation as potential mechanisms through which TBI can initiate or accelerate PD. Amyloid precursor protein (APP), alpha synuclein (α-syn), hyper-phosphorylated Tau, and TAR DNA-binding protein 43 (TDP-43), are some of the most frequently reported proteins upregulated following a TBI and are also closely linked to PD. Recently, upregulation of Leucine Rich Repeat Kinase 2 (LRRK2), has been found in the brain of mice following a TBI. Subset of Rab proteins were identified as biological substrates of LRRK2, a protein also extensively linked to late onset PD. Inhibition of LRRK2 was found to be neuroprotective in PD and TBI models. The goal of this review is to survey current literature concerning the mechanistic overlap between TBI and PD with a particular focus on inflammation, metabolic dysregulation, and aforementioned proteins. This review will also cover the application of rodent TBI models to further our understanding of the relationship between TBI and PD.

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Section: Controlled Cortical Impact (Cci) Tbimentioning

confidence: 98%

Section: Controlled Cortical Impact (Cci) Tbimentioning

confidence: 99%

Biological links between traumatic brain injury and Parkinson’s disease

Delic

Beck

Pang

et al. 2020

acta neuropathol commun

View full text Add to dashboard Cite

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“…Loss of the LRRK2 gene in aged mice has been demonstrated to impair the autophagy-lysosome pathway, which leads to marked accumulation of α-synuclein and ubiquitinated proteins (Tong et al ., 2010). Moreover, HIF-1α can bind to the LRRK2 promoter region, leading to transcriptional induction of LRRK2 (Bae et al ., 2018). Notch inhibition may be mediated by the LRRK2 complex, harboring ROC pathogenic mutations (Imai et al ., 2015).…”

Section: Hif and Notch In Neurological Disordersmentioning

confidence: 99%

The Role of a Neurovascular Signaling Pathway Involving Hypoxia-Inducible Factor and Notch in the Function of the Central Nervous System

Kim

Lee

Choi

2020

Biomolecules & Therapeutics

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In the neurovascular unit, the neuronal and vascular systems communicate with each other. O2 and nutrients, reaching endothelial cells (ECs) through the blood stream, spread into neighboring cells, such as neural stem cells, and neurons. The proper function of neural circuits in adults requires sufficient O2 and glucose for their metabolic demands through angiogenesis. In a central nervous system (CNS) injury, such as glioma, Parkinson's disease, and Alzheimer's disease, damaged ECs can contribute to tissue hypoxia and to the consequent disruption of neuronal functions and accelerated neurodegeneration. This review discusses the current evidence regarding the contribution of oxygen deprivation to CNS injury, with an emphasis on hypoxia-inducible factor (HIF)-mediated pathways and Notch signaling. Additionally, it focuses on adult neurological functions and angiogenesis, as well as pathological conditions in the CNS. Furthermore, the functional interplay between HIFs and Notch is demonstrated in pathophysiological conditions.

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“…The JAK-STAT signalling pathway has the dual functions of signal transduction and transcriptional regulation and plays an important role in regulating cell proliferation, immune regulation, in ammation, tumours, and other pathophysiological processes. The JAK-STAT signalling pathway is activated in brain tissue after TBI and aggravates the destruction of the blood-brain barrier and nerve damage [34] .…”

Section: Discussionmentioning

confidence: 99%

Tittle Exploring the Mechanism of Resveratrol on Traumatic Brain Injury by Network Pharmacology and Molecular Docking

Liu¹,

Li-jun²,

Li³

et al. 2020

Preprint

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[Background] Resveratrol is a polyphenol present abundantly in lots of traditional Chinese medicines, which has been shown to have beneficial effects on neurological diseases. However, the molecular mechanisms of resveratrol on traumatic brain injury have not been systematically studied yet. In this study, we elucidated the pharmacological mechanisms of resveratrol in treating traumatic brain injury by using a network pharmacology method. [Methods] The pharmacokinetics properties of resveratrol were obtained from the traditional Chinese medicine systems pharmacology database and analysis platform (TCMSP). The putative targets of resveratrol were obtained from TCMSP, BATMAN-TCM, SuperPred, PharmMapper, SwissTargetPrediction, DrugBank, and a literature search. The targets related to traumatic brain injury were obtained from TTD, DrugBank, CTD, GeneCards, OMIM, MalaCards, and a literature search. The STRING database and the Cytoscape 3.8.0 software were used to build the protein-protein interaction (PPI) network. The Metascape database was used to obtain the gene ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment information. Finally, The AutoDockTools 1.5.6 and PyMOL 2.4.0 software were employed for molecular docking analyses, and Discovery Studio 2020 was used for interaction analyses. [Results] A total of 165 overlapping targets involved in resveratrol intervention in traumatic brain injury were determined. The GO function analysis indicated that the targets are including the positive regulation of transferase activity, the positive regulation of cell migration, reactive oxygen species metabolism, the wound response, and so on. The KEGG pathway analysis identified the following enriched pathways: the AGE-RAGE signalling pathway, the FoxO signalling pathway, insulin resistance, complement and coagulation cascades, the HIF-1 signalling pathway, and so on. According to the PPI network analysis, INS, IGF1, TNF, TP53, ALB, IL6, SRC, STAT3, VEGFA, and MMP9 were identified as hub target genes, in which IL6, MMP9, INS, and SRC showed a good binding affinity with resveratrol in molecular docking. [Conclusions] Resveratrol may target multiple genes and multiple pathways to reduce brain damage after traumatic brain injury.

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Brain injury induces HIF-1α-dependent transcriptional activation of LRRK2 that exacerbates brain damage

Cited by 44 publications

References 62 publications

Biological links between traumatic brain injury and Parkinson’s disease

Biological links between traumatic brain injury and Parkinson’s disease

The Role of a Neurovascular Signaling Pathway Involving Hypoxia-Inducible Factor and Notch in the Function of the Central Nervous System

Tittle Exploring the Mechanism of Resveratrol on Traumatic Brain Injury by Network Pharmacology and Molecular Docking

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