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Neuron/glial 2 (NG2)‐expressing cells are often referred to as oligodendrocyte precursor cells. NG2‐expressing cells have also been identified as multipotent progenitor cells. However, microglia‐like NG2 glial cells have not been fully examined in neurodegenerative disorders such as Parkinson's disease (PD). In the present study, we chose two rat models of PD, i.e., intranigral or intrastriatal injection...
Our previous studies demonstrated the involvement of quinone formation in dopaminergic neuron dysfunction in the L‐DOPA‐treated parkinsonian model and in methamphetamine (METH) neurotoxicity. We further reported that the cysteine‐rich metal‐binding metallothionein (MT) family of proteins protects dopaminergic neurons against dopamine (DA) quinone neurotoxicity by its quinone‐quenching property. The...
It is well accepted that CNS inflammation has a role in the progression of chronic neurodegenerative disease, although the mechanisms through which this occurs are still unclear. The inflammatory response during most chronic neurodegenerative disease is dominated by the microglia and mechanisms by which these cells contribute to neuronal damage and degeneration are the subject of intense study. More...
PINK1 (PTEN induced putative kinase 1), a familial Parkinson's disease (PD)‐related gene, is expressed in astrocytes, but little is known about its role in this cell type. Here, we found that astrocytes cultured from PINK1‐knockout (KO) mice exhibit defective proliferative responses to epidermal growth factor (EGF) and fetal bovine serum. In PINK1‐KO astrocytes, basal and EGF‐induced p38 activation...
Increasing evidence suggests that Parkinson's disease (PD)‐linked Leucine‐rich repeat kinase 2 (LRRK2) has a role in peripheral and brain‐resident immune cells. Furthermore, dysregulation of the anti‐inflammatory, neurotrophic protein progranulin (PGRN) has been demonstrated in several chronic neurodegenerative diseases. Here we show that PGRN levels are significantly reduced in conditioned medium...
Activation of microglial NADPH oxidase (NOX2) plays a critical role in mediating neuroinflammation, which is closely linked with the pathogenesis of a variety of neurodegenerative diseases, including Parkinson's disease (PD). The inhibition of NOX2‐generated superoxide has become an effective strategy for developing disease‐modifying therapies for PD. However, the lack of specific and potent NOX2...
Parkinson's disease (PD) is the second most common neurodegenerative disease and results from the loss of dopaminergic neurons of the nigrostriatal pathway. The pathogenesis of PD is poorly understood, but inflammatory processes have been implicated. Indeed increases in the number of major histocompatibility complex II (MHC II) reactive cells have long been recognised in the brains of PD patients...
Activation of microglia resulting in exacerbated inflammation expression plays an important role in degeneration of dopaminergic (DA) neurons in the pathogenesis of Parkinson's disease (PD). However, how this enhanced inflammation is induced in microglia remains largely unclear. Here, in the mouse PD model induced by 1‐methyl‐4‐phenyl‐1,2,3,6‐tetra hydropyridine (MPTP), we found that miR‐7116‐5p in...
Neuroinflammation mediated by chronically activated microglia, largely caused by abnormal accumulation of misfolded α‐synuclein (αSyn) protein, is known to contribute to the pathophysiology of Parkinson's disease (PD). In this work, based on the immunomodulatory activities displayed by particular heat‐shock proteins (HSPs), we tested a novel vaccination strategy that used a combination of αSyn and...
Defects in repair of damaged brain accumulate injury and contribute to slow‐developing neurodegeneration. Here, we report that a deficiency of DJ‐1, a Parkinson's disease (PD) gene, delays repair of brain injury due to destabilization of Sox9, a positive regulator of astrogliosis. Stereotaxic injection of ATP into the brain striatum produces similar size of acute injury in wild‐type and DJ‐1‐knockout...
Neuroinflammation and mitochondrial dysfunction, key mechanisms in the pathogenesis of Parkinson's disease (PD), are usually explored independently. Loss‐of‐function mutations of PARK2 and PARK6, encoding the E3 ubiquitin protein ligase Parkin and the mitochondrial serine/threonine kinase PINK1, account for a large proportion of cases of autosomal recessive early‐onset PD. PINK1 and Parkin regulate...
Parkinson's disease (PD) is characterized by the selective degeneration of dopamine (DA) neurons of the substantia nigra pars compacta (SN), while the neighboring ventral tegmental area (VTA) is relatively spared. The mechanisms underlying this selectivity are not fully understood. Here, we demonstrate a vital role for subregional astrocytes in the protection of VTA DA neurons. We found that elimination...
α‐Synucleinopathies are neurodegenerative diseases that are characterized pathologically by α‐synuclein inclusions in neurons and glia. The pathologic contribution of glial α‐synuclein in these diseases is not well understood. Glial α‐synuclein may be of particular importance in multiple system atrophy (MSA), which is defined pathologically by glial cytoplasmic α‐synuclein inclusions. We have previously...
Microglia‐mediated neuroinflammation is a crucial pathophysiological contributor to several aging‐related neurodegenerative disorders, including Parkinson's disease (PD). During the process of aging or stress, microglia undergoes several transcriptional and morphological changes that contribute to aberrant immunological responses, which is known as priming. Key molecules involved in the process, however,...
Microglia are a specialized population of tissue macrophages in the mammalian brain. Microglial phenotype is tightly regulated by local environmental factors, although little is known about these factors and their region‐preferred roles in regulating local neuroinflammatory responses. We hypothesized that microglia in different brain regions respond differently to neuroinflammatory stimulation and...
Monocyte‐derived macrophages play a role in the repair of the injured brain. We previously reported that a deficiency of the Parkinson's disease (PD)‐associated gene DJ‐1 delays repair of brain injury produced by stereotaxic injection of ATP, a component of damage‐associated molecular patterns. Here, we show that a DJ‐1 deficiency attenuates monocyte infiltration into the damaged brain owing to a...
Nuclear receptor‐related 1 protein (NURR1) is essential for the development and maintenance of midbrain dopaminergic (DAergic) neurons. NURR1 also protects DAergic neurons against neuroinflammation. However, it remains to be determined to what extent does NURR1 exerts its protective function through acting autonomously in the microglia. Using Cre/lox gene targeting system, we deleted Nurr1 in the...
During aging humans lose midbrain dopamine neurons, but not all dopamine regions exhibit vulnerability to neurodegeneration. Microglia maintain tissue homeostasis and neuronal support, but microglia become senescent and likely lose some of their functional abilities. Since aging is the greatest risk factor for Parkinson's disease, we hypothesized that aging‐related changes in microglia and neurons...
Mitophagy is essential for the health of dopaminergic neurons because mitochondrial damage is a keystone of Parkinson's disease. The aim of the present work was to study the degradation of mitochondria in the degenerating dopaminergic synapse. Adult Sprague–Dawley rats and YFP‐Mito‐DAn mice with fluorescent mitochondria in dopaminergic neurons were injected in the lateral ventricles with 6‐hydroxydopamine,...
The progressive neuropathological damage seen in Parkinson's disease (PD) is thought to be related to the spreading of aggregated forms of α‐synuclein. Clearance of extracellular α‐synuclein released by degenerating neurons may be therefore a key mechanism to control the concentration of α‐synuclein in the extracellular space. Several molecular chaperones control misfolded protein accumulation in...
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