<scp>A</scp><scp>P</scp>arkinson's disease gene, <scp>DJ</scp>‐1, repairs brain injury through <scp>S</scp>ox9 stabilization and astrogliosis

Choi, Dong‐Joo; Eun, Jin-Hwa; Kim, Byung Gon; Jou, Ilo; Park, Sang Myun; Joe, Eun‐Hye

doi:10.1002/glia.23258

Cited by 38 publications

(30 citation statements)

References 69 publications

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“…The transcription factor Sox9 is expressed primarily by astrocytes and is upregulated in reactive astrocytes in models of stroke and Parkinson's disease (Choi et al, 2018;Sun et al, 2017). We tested for Sox9 expression in astrocytes adjacent to regions of ablation but found that Sox9 expression remained unchanged in all groups (Fig.…”

Section: Astrocytes Adjacent To Ablated Areas Respond With Molecular mentioning

confidence: 99%

Astrocytes are necessary for blood-brain barrier maintenance in the adult mouse brain

Heithoff

George

Phares

et al. 2020

Preprint

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224/250 words)In the adult brain, multiple cell types are known to produce factors that regulate blood-brain barrier properties, including astrocytes. Yet several recent studies disputed a role for mature astrocytes at the blood-brain barrier. To determine if astrocytes contribute a non-redundant and necessary function in maintaining the adult blood-brain barrier, we used a mouse model of tamoxifen-inducible astrocyte ablation. In adult mice, tamoxifen induction caused sparse apoptotic astrocyte cell death within 2 hours. Indicative of BBB damage, leakage of the small molecule Cadaverine and the large plasma protein fibrinogen into the brain parenchyma indicative of BBB damage was detected as early as astrocyte ablation was present. Vessels within and close to regions of astrocyte loss had lower expression of the tight junction protein zonula occludens-1 while endothelial glucose transporter 1 expression was undisturbed.Cadaverine leakage persisted for several weeks suggesting a lack of barrier repair. This is consistent with the finding that ablated astrocytes were not replaced. Adjacent astrocytes responded with partial non-proliferative astrogliosis, characterized by morphological changes and delayed phosphorylation of STAT3, which restricted dye leakage to the brain and vessel surface areas lacking coverage by astrocytes one month after ablation. In conclusion, astrocytes are necessary to maintain blood-brain barrier integrity in the adult brain. Blood-brain barrier-regulating factors secreted by other cell types, such as pericytes, are not sufficient to compensate for astrocyte loss. Main Points (250 characters)Mature astrocytes are necessary for maintenance of endothelial tight junctions in the adult brain.Ablated astrocytes are not replaced by proliferation or process extension of neighboring astrocytes resulting in long-term blood-brain barrier damage.

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Section: Astrocytes Adjacent To Ablated Areas Respond With Molecular mentioning

confidence: 99%

Astrocytes are necessary for blood-brain barrier maintenance in the adult mouse brain

Heithoff

George

Phares

et al. 2020

Preprint

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“…Growth factors released from astrocytes including glial-derived neurotrophic factor (GDNF), brain-derived neurotrophic factor (BDNF), etc., are important for the development and survival of neurons [ 117 118 ]. Recently, we have reported that DJ-1 deficiency reduces GDNF and BDNF expression in astrocytes [ 119 ]. Several studies have reported that parkin and PINK1 are linked to the expression and/or functions of GDNF.…”

Section: Functions Of Astrocytes and Microglia Are Altered By Mutatiomentioning

confidence: 99%

“…Astrocytes proliferate and participate in repairing the damage in injured brain [ 57 122 ]. Our recent study shows that DJ-1 positively regulates astrogliosis in injured brain [ 119 ]. DJ-1 regulates astrogliosis through stabilization of Sox9 [ 119 ], a transcription factor that regulates gliogenesis during development of the brain [ 123 124 ], and astogliosis in injured brain [ 125 126 ].…”

Section: Functions Of Astrocytes and Microglia Are Altered By Mutatiomentioning

confidence: 99%

Astrocytes, Microglia, and Parkinson’s Disease

et al. 2018

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Astrocytes and microglia support well-being and well-function of the brain through diverse functions in both intact and injured brain. For example, astrocytes maintain homeostasis of microenvironment of the brain through up-taking ions and neurotransmitters, and provide growth factors and metabolites for neurons, etc. Microglia keep surveying surroundings, and remove abnormal synapses or respond to injury by isolating injury sites and expressing inflammatory cytokines. Therefore, their loss and/or functional alteration may be directly linked to brain diseases. Since Parkinson's disease (PD)-related genes are expressed in astrocytes and microglia, mutations of these genes may alter the functions of these cells, thereby contributing to disease onset and progression. Here, we review the roles of astrocytes and microglia in intact and injured brain, and discuss how PD genes regulate their functions.

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“…This included SOD1, glutathione synthetase (GSS), and dimethylarginine dimethylaminohydrolase 1 (DDAH1) of the validated myelination panel, which all function to clear damaging free radicals [59][60][61][62]. Likewise, the validated glial immunity panel included PARK7 or DJ-1, yet another mediator of oxidative stress in the brain [63,64]. Finally, highly validated markers of the vascular panel included paroxonase 1 (PON1), a lipoprotein-binding enzyme responsible for reducing oxidative stress levels in the circulation [65,66].…”

Section: Csf Biomarkers Of Brain-linked Panels Validate In a Replicatmentioning

confidence: 99%

Integrated Proteomics Reveals Brain-Based Cerebrospinal Fluid Biomarkers in Asymptomatic and Symptomatic Alzheimer’s Disease

Higginbotham

Ping

Dammer

et al. 2019

Preprint

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Our results used an integrative proteomic approach to identify panels of CSF AD protein biomarkers with strong links to a variety of pathological mechanisms in the diseased brain.Abstract: Alzheimer's disease (AD) features a complex web of pathological processes beyond amyloid accumulation and tau-mediated neuronal death. To meaningfully advance AD therapeutics, there is an urgent need for novel biomarkers that comprehensively reflect these disease mechanisms. Here we applied an integrative proteomics approach to identify cerebrospinal fluid (CSF) biomarkers linked to a diverse set of pathophysiological processes in the diseased brain. Using multiplex proteomics, we identified >3,500 proteins across 40 CSF samples from control and AD patients and >12,000 proteins across 48 postmortem brain tissues from control, asymptomatic AD (AsymAD), AD, and other neurodegenerative cases. Co-expression network analysis of the brain tissues resolved 44 protein modules, nearly half of which significantly correlated with AD neuropathology. Fifteen modules robustly overlapped with proteins quantified in the CSF, including 271 CSF markers highly altered in AD. These 15 overlapping modules were collapsed into five panels of brain-linked fluid markers representing a variety of cortical functions. Neuron-enriched synaptic and metabolic panels demonstrated decreased levels in the AD brain but increased levels in diseased CSF. Conversely, glial-enriched myelination and immunity panels were highly increased in both the brain and CSF. Using high-throughput proteomic analysis, proteins from these panels were validated in an independent CSF cohort of control, AsymAD, and AD samples. Remarkably, several validated markers were significantly altered in AsymAD CSF and appeared to stratify subpopulations within this cohort. Overall, these brain-linked CSF biomarker panels represent a promising step toward a physiologically comprehensive tool that could meaningfully enhance the prognostic and therapeutic management of AD.

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AParkinson's disease gene, DJ‐1, repairs brain injury through Sox9 stabilization and astrogliosis

Cited by 38 publications

References 69 publications

Astrocytes are necessary for blood-brain barrier maintenance in the adult mouse brain

Astrocytes are necessary for blood-brain barrier maintenance in the adult mouse brain

Astrocytes, Microglia, and Parkinson’s Disease

Integrated Proteomics Reveals Brain-Based Cerebrospinal Fluid Biomarkers in Asymptomatic and Symptomatic Alzheimer’s Disease

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