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Parkinson Disease: HELP
Articles by Ning-Ning Song
Based on 21 articles published since 2010
(Why 21 articles?)
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Between 2010 and 2020, Ning Song wrote the following 21 articles about Parkinson Disease.
 
+ Citations + Abstracts
1 Review Iron Pathophysiology in Parkinson Diseases. 2019

Jiang, Hong / Song, Ning / Jiao, Qian / Shi, Limin / Du, Xixun. ·Department of Physiology, Medical College of Qingdao University, Qingdao, 266071, China. hongjiang@qdu.edu.cn. · Department of Physiology, Medical College of Qingdao University, Qingdao, 266071, China. ·Adv Exp Med Biol · Pubmed #31456205.

ABSTRACT: The key molecular events that provoke Parkinson's disease (PD) are not fully understood. Iron deposit was found in the substantia nigra pars compacta (SNpc) of PD patients and animal models, where dopaminergic neurons degeneration occurred selectively. The mechanisms involved in disturbed iron metabolism remain unknown, however, considerable evidence indicates that iron transporters dysregulation, activation of L-type voltage-gated calcium channel (LTCC) and ATP-sensitive potassium (KATP) channels, as well as N-methyl-D-aspartate (NMDA) receptors (NMDARs) contribute to this process. There is emerging evidence on the structural links and functional modulations between iron and α-synuclein, and the key player in PD which aggregates in Lewy bodies. Iron is believed to modulate α-synuclein synthesis, post-translational modification, and aggregation. Furthermore, glia, especially activated astroglia and microglia, are involved in iron deposit in PD. Glial contributions were largely dependent on the factors they released, e.g., neurotrophic factors, pro-inflammatory factors, lactoferrin, and those undetermined. Therefore, iron chelation using iron chelators, the extracts from many natural foods with iron chelating properties, may be an effective therapy for prevention and treatment of the disease.

2 Review Iron Dysregulation in Parkinson's Disease: Focused on the Autophagy-Lysosome Pathway. 2019

Chen, Lei-Lei / Huang, Yu-Jv / Cui, Jun-Tao / Song, Ning / Xie, Junxia. ·Institute of Brain Science and Disease, Shandong Provincial Collaborative Innovation Center for Neurodegenerative Disorders, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders , Qingdao University , Qingdao , Shandong 266071 , China. ·ACS Chem Neurosci · Pubmed #30590010.

ABSTRACT: Parkinson's disease (PD) is the second most common neurodegenerative disease and is characterized by dopaminergic neuron loss in the substantia nigra pars compacta (SNpc). Although both iron accumulation and a defective autophagy-lysosome pathway contribute to the pathological development of PD, the connection between these two causes is poorly documented. The autophagy-lysosome pathway not only responds to regulation by iron chelators and channels but also participates in cellular iron recycling through the degradation of ferritin and other iron-containing components. Previously, ferritin has been posited to be the bridge between iron accumulation and autophagy impairment in PD. In addition, iron directly interacts with α-synuclein in Lewy bodies, which are primarily digested through the autophagy-lysosome pathway. These findings indicate that some link exists between iron deposition and autophagy impairment in PD. In this review, the basic mechanisms of the autophagy-lysosome pathway and iron trafficking are introduced, and then their interaction under physiological conditions is explained. Finally, we finish by discussing the dysfunction of iron deposition and autophagy in PD, as well as their potential relationship, which will provide some insight for further study.

3 Review [GBA mutations and Parkinson's disease]. 2018

Wang, Dong-Xia / Xie, Jun-Xia / Song, Ning. ·Department of Physiology and Pathophysiology, Institute of Brain Science and Disease, Medical College of Qingdao University, Qingdao 266071, China. · Department of Physiology and Pathophysiology, Institute of Brain Science and Disease, Medical College of Qingdao University, Qingdao 266071, China. ningsong@qdu.edu.cn. ·Sheng Li Xue Bao · Pubmed #29926071.

ABSTRACT: Parkinson's disease (PD) is a common neurodegenerative disease characterized by the degeneration of dopaminergic neurons in the substantia nigra and the intraneuronal Lewy bodies in this area. Genetic mutations in PD pathogenesis have been explored and better understood in recent years. GBA variants are now considered to be the single largest risk factor for PD. Gaucher disease (GD) is a lysosomal storage disorder disease and an inherited deficiency of lysosomal glucocerebrosidase (GCase) arising from mutations in the gene GBA. A group of patients with GD exhibit parkinsonian symptoms, meanwhile, GBA mutations are more frequently observed in patients with PD. These lines of evidence suggest a close relationship between GBA mutations and PD. GBA mutations are associated with an earlier onset age and a distinct cognitive decline in PD. GCase loss-of-function caused by GBA mutations interferes with the degradation of α-synuclein, and α-synuclein pathology in turn inhibits normal GCase function in PD, which forms a vicious cycle. However, the exact mechanisms for this bidirectional pathogenic loop have not to be fully elucidated. In this review, we summarize the current understandings on the potential link between GBA mutations and PD pathogenesis, which may show novel insights into PD etiology and therapeutics.

4 Review Astroglial and microglial contributions to iron metabolism disturbance in Parkinson's disease. 2018

Song, Ning / Wang, Jun / Jiang, Hong / Xie, Junxia. ·Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines: Physiology, Medical College of Qingdao University, Qingdao 266071, China; Institute of Brain Science and Disease, Qingdao University, Qingdao 266071, China. Electronic address: ningsong@qdu.edu.cn. · Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines: Physiology, Medical College of Qingdao University, Qingdao 266071, China; Institute of Brain Science and Disease, Qingdao University, Qingdao 266071, China. · Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines: Physiology, Medical College of Qingdao University, Qingdao 266071, China; Institute of Brain Science and Disease, Qingdao University, Qingdao 266071, China. Electronic address: jxiaxie@public.qd.sd.cn. ·Biochim Biophys Acta Mol Basis Dis · Pubmed #29317336.

ABSTRACT: Understandings of the disturbed iron metabolism in Parkinson's disease (PD) are largely from the perspectives of neurons. Neurodegenerative processes in PD trigger universal and conserved astroglial dysfunction and microglial activation. In this review, we start with astroglia and microglia in PD with an emphasis on their roles in spreading α-synuclein pathology, and then focus on their contributions in iron metabolism under normal conditions and the diseased state of PD. Elevated iron in the brain regions affects glial features, meanwhile, glial effects on neuronal iron metabolism are largely dependent on their releasing factors. These advances might be valuable for better understanding and modulating iron metabolism disturbance in PD.

5 Review New Progress on the Role of Glia in Iron Metabolism and Iron-Induced Degeneration of Dopamine Neurons in Parkinson's Disease. 2017

Xu, Huamin / Wang, Youcui / Song, Ning / Wang, Jun / Jiang, Hong / Xie, Junxia. ·Collaborative Innovation Center for Brain Science, Department of Physiology, Shandong Provincial Collaborative Innovation Center for Neurodegenerative Disorders, Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines: Physiology, Medical College of Qingdao University, Qingdao, China. ·Front Mol Neurosci · Pubmed #29403352.

ABSTRACT: It is now increasingly appreciated that glial cells play a critical role in the regulation of iron homeostasis. Impairment of these properties might lead to dysfunction of iron metabolism and neurodegeneration of neurons. We have previously shown that dysfunction of glia could cause iron deposit and enhance iron-induced degeneration of dopamine (DA) neurons in Parkinson's disease (PD). There also has been a substantial growth of knowledge regarding the iron metabolism of glia and their effects on iron accumulation and degeneration of DA neurons in PD in recent years. Here, we attempt to describe the role of iron metabolism of glia and the effect of glia on iron accumulation and degeneration of DA neurons in the substantia nigra of PD. This could provide evidence to reveal the mechanisms underlying nigral iron accumulation of DA neurons in PD and provide the basis for discovering new potential therapeutic targets for PD.

6 Review [Glial cells are involved in iron accumulation and degeneration of dopamine neurons in Parkinson's disease]. 2016

Xu, Hua-Min / Wang, Jun / Song, Ning / Jiang, Hong / Xie, Jun-Xia. ·Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders, Shandong Provincial Collaborative Innovation Center for Neurodegenerative Disorders, Medical College of Qingdao University, Qingdao 266071, China. · Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders, Shandong Provincial Collaborative Innovation Center for Neurodegenerative Disorders, Medical College of Qingdao University, Qingdao 266071, China. jxiaxie@public.qd.sd.cn. ·Sheng Li Xue Bao · Pubmed #27546505.

ABSTRACT: A growing body of evidence suggests that glial cells play an important role in neural development, neural survival, nerve repair and regeneration, synaptic transmission and immune inflammation. As the highest number of cells in the central nervous system, the role of glial cells in Parkinson's disease (PD) has attracted more and more attention. It has been confirmed that nigral iron accumulation contributes to the death of dopamine (DA) neurons in PD. Until now, most researches on nigral iron deposition in PD are focusing on DA neurons, but in fact glial cells in the central nervous system also play an important role in the regulation of iron homeostasis. Therefore, this review describes the role of iron metabolism of glial cells in death of DA neurons in PD, which could provide evidence to reveal the mechanisms underlying nigral iron accumulation of DA neurons in PD and provide the basis for discovering new potential therapeutic targets for PD.

7 Review [The Role of Iron and Alpha-synuclein Interacting in Parkinson's Disease]. 2015

Wang, Jun / Song, Ning / Xu, Hua-min / Jiang, Hong / Xie, Jun-xia. · ·Sheng Li Ke Xue Jin Zhan · Pubmed #26521482.

ABSTRACT: Both iron and alpha-synuclein accumulation are one of hallmarks of Parkinson's disease (PD). Alpha-synuclein aggregation is often accompanied by abnormal accumulation of iron, indicating that there is a certain link between iron and alpha-synuclein aggregation. Iron promotes alpha-synuclein aggregation by increasing its synthesis and decreasing its degradation. Also, alpha-synuclein regulates iron metabolism through its ferrireductase activity. In this review, we will describe the roles of iron and alpha-synuclein in PD pathogenesis, and the mechanisms of iron and alpha-synuclein interaction.

8 Article Iron-induced oxidative stress contributes to α-synuclein phosphorylation and up-regulation via polo-like kinase 2 and casein kinase 2. 2019

Wang, Ranran / Wang, Youcui / Qu, Le / Chen, Bingbing / Jiang, Hong / Song, Ning / Xie, Junxia. ·Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders, Medical College of Qingdao University, Qingdao, 266071, China; Institute of Brain Science and Disease, Qingdao University, Qingdao, 266071, China. · Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders, Medical College of Qingdao University, Qingdao, 266071, China; Institute of Brain Science and Disease, Qingdao University, Qingdao, 266071, China. Electronic address: ningsong@qdu.edu.cn. · Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders, Medical College of Qingdao University, Qingdao, 266071, China; Institute of Brain Science and Disease, Qingdao University, Qingdao, 266071, China. Electronic address: jxiaxie@public.qd.sd.cn. ·Neurochem Int · Pubmed #30797969.

ABSTRACT: α-Synuclein plays a central role in synucleinopathies pathogenesis such as Parkinson's disease (PD). Phosphorylation is the most common and important protein modification linked to α-synuclein pathologies. There is mounting evidence suggested iron and α-synuclein are closely related in PD. We previously reported iron up-regulated α-synuclein mRNA levels and induced α-synuclein aggregation. In the present study, we aimed to investigate whether and how phosphorylation was involved in iron-induced α-synuclein regulations. The results showed that iron could induce pS129 α-synuclein (phosphorylation at Ser129) and α-synuclein upregulation in the substantia nigra of iron-overloaded rats and iron-treated SH-SY5Y cells, accompanied by the elevated levels of polo-like kinase 2 (PLK2) and casein kinase 2 (CK2). Over-expression of CK2 or PLK2 induced pS129 α-synuclein up-regulation and inhibitors of CK2 or PLK2 could suppress iron-induced α-synuclein phosphorylation. Antioxidant NAC could fully block iron-induced upregulation of CK2, PLK2 and pS129 α-synuclein levels, indicating oxidative stress plays a critical role in iron-induced α-synuclein phosphorylation. However, iron-induced α-synuclein up-regulation could only be partially blocked by CK2/PLK2 inhibitor or NAC. These findings demonstrate that iron-induced oxidative stress is largely responsible for α-synuclein phosphorylation and upregulation via CK2 and PLK2, and α-synuclein upregulation is not fully phosphorylation-dependent.

9 Article High Dietary Iron Supplement Induces the Nigrostriatal Dopaminergic Neurons Lesion in Transgenic Mice Expressing Mutant A53T Human Alpha-Synuclein. 2018

Jia, Fengju / Song, Ning / Wang, Weiwei / Du, Xixun / Chi, Yajing / Jiang, Hong. ·Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines: Physiology, Medical College of Qingdao University, Qingdao, China. ·Front Aging Neurosci · Pubmed #29681846.

ABSTRACT: Both alpha-synuclein aggregation and iron deposits are neuropathological hallmarks of Parkinson's disease (PD). We are particularly interested in whether iron could synergize with alpha-synuclein pathology

10 Article Iron, Dopamine, and α-Synuclein Interactions in at-Risk Dopaminergic Neurons in Parkinson's Disease. 2018

Song, Ning / Xie, Junxia. ·Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines: Physiology, Medical College of Qingdao University, Qingdao, 266071, China. · Institute of Brain Science and Disease, Qingdao University, Qingdao, 266071, China. · Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines: Physiology, Medical College of Qingdao University, Qingdao, 266071, China. jxiaxie@163.com. · Institute of Brain Science and Disease, Qingdao University, Qingdao, 266071, China. jxiaxie@163.com. ·Neurosci Bull · Pubmed #29380248.

ABSTRACT: -- No abstract --

11 Article Genomic DNA levels of mutant alpha-synuclein correlate with non-motor symptoms in an A53T Parkinson's disease mouse model. 2018

Wang, Weiwei / Song, Ning / Jia, Fengjv / Tang, Tingting / Bao, Weiqi / Zuo, Chuantao / Xie, Junxia / Jiang, Hong. ·Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines: Physiology, Medical College of Qingdao University, Qingdao 266071, China. · PET Center, Huashan Hospital of Fudan University, Shanghai 200235, China. · Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines: Physiology, Medical College of Qingdao University, Qingdao 266071, China. Electronic address: hongjiang@qdu.edu.cn. ·Neurochem Int · Pubmed #29355568.

ABSTRACT: Alpha-synuclein plays a key role in the pathogenesis of Parkinson's disease (PD). A robust transgenic mouse model has been generated that overexpresses the mutant human A53T alpha-synuclein under the mouse prion protein gene promoter; these mice develop age-dependent motor deficits. Recently, compared to wild-type (WT) littermates, A53T alpha-synuclein mice were reported to display non-motor symptom deficits, e.g., anxiety-like and depressive-like behaviors, odor discrimination and detection impairments, and gastrointestinal dysfunction, at 6 months of age or older. However, the differences between heterozygous and homozygous mice in terms of non-motor symptoms and whether the genomic DNA levels of alpha-synuclein correlate with the symptoms have not yet been elucidated. In the present work, we used littermate WT and heterozygous and homozygous A53T mice that were characterized by a modified genotyping protocol and observed a unilateral decline in the dopamine transporter (DAT) distribution from 3 months to 12 months of age in homozygous mice. We evaluated non-motor symptoms by measuring colon motility, anxiety-like and depressive-like behaviors, and motor coordination. The results showed that homozygous A53T mice exhibited earlier abnormal non-motor symptoms compared to their heterozygous littermates. The severity of impaired colon motility as well as anxiety-like and depressive-like behaviors were correlated with the genomic DNA levels of A53T mutant alpha-synuclein. More noticeable, motor coordination aberrances were also observed in homozygous A53T mice. This study provides direct evidence that the genomic DNA levels of mutant alpha-synuclein correlate with non-motor symptoms in an A53T mouse model, indicating that the genomic DNA levels of mutant alpha-synuclein should be tightly manipulated in PD model studies.

12 Article Transmission of α-synuclein-containing erythrocyte-derived extracellular vesicles across the blood-brain barrier via adsorptive mediated transcytosis: another mechanism for initiation and progression of Parkinson's disease? 2017

Matsumoto, Junichi / Stewart, Tessandra / Sheng, Lifu / Li, Na / Bullock, Kristin / Song, Ning / Shi, Min / Banks, William A / Zhang, Jing. ·Department of Pathology, University of Washington School of Medicine, Seattle, WA, 98104, USA. · Department of Pathology, Peking University Health Science Centers, Beijing, 100191, China. · Geriatrics Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA, 98108, USA. · Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington School of Medicine, Seattle, WA, 98108, USA. · Department of Pathology, University of Washington School of Medicine, Seattle, WA, 98104, USA. zhangj@uw.edu. · Department of Pathology, Peking University Health Science Centers, Beijing, 100191, China. zhangj@uw.edu. ·Acta Neuropathol Commun · Pubmed #28903781.

ABSTRACT: Parkinson's disease (PD) pathophysiology develops in part from the formation, transmission, and aggregation of toxic species of the protein α-synuclein (α-syn). Recent evidence suggests that extracellular vesicles (EVs) may play a vital role in the transport of toxic α-syn between brain regions. Moreover, increasing evidence has highlighted the participation of peripheral molecules, particularly inflammatory species, which may influence or exacerbate the development of PD-related changes to the central nervous system (CNS), although detailed characterization of these species remains to be completed. Despite these findings, little attention has been devoted to erythrocytes, which contain α-syn concentrations ~1000-fold higher than the cerebrospinal fluid, as a source of potentially pathogenic α-syn. Here, we demonstrate that erythrocytes produce α-syn-rich EVs, which can cross the BBB, particularly under inflammatory conditions provoked by peripheral administration of lipopolysaccharide. This transport likely occurs via adsorptive-mediated transcytosis, with EVs that transit the BBB co-localizing with brain microglia. Examination of microglial reactivity upon exposure to α-syn-containing erythrocyte EVs in vitro and in vivo revealed that uptake provoked an increase in microglial inflammatory responses. EVs derived from the erythrocytes of PD patients elicited stronger responses than did those of control subjects, suggesting that inherent characteristics of EVs arising in the periphery might contribute to, or even initiate, CNS α-syn-related pathology. These results provide new insight into the mechanisms by which the brain and periphery communicate throughout the process of synucleinopathy pathogenesis.

13 Article Assessments of plasma ghrelin levels in the early stages of parkinson's disease. 2017

Song, Ning / Wang, Weiwei / Jia, Fengjv / Du, Xixun / Xie, Anmu / He, Qing / Shen, Xiaoli / Zhang, Jing / Rogers, Jack T / Xie, Junxia / Jiang, Hong. ·Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines: Physiology, Medical College of Qingdao University, Qingdao, China. · Department of Neurology, the Affiliated Hospital of Qingdao University, Qingdao, China. · Department of Pathology, University of Washington School of Medicine, Seattle, Washington, USA. · Neurochemistry Laboratory, Department of Psychiatry-Neuroscience, Massachusetts General Hospital (East), Harvard Medical School, Charlestown, Masssachusetts, USA. ·Mov Disord · Pubmed #28681931.

ABSTRACT: BACKGROUND: Gastrointestinal symptoms are early events in Parkinson's disease (PD). The gastrointestinal hormone ghrelin was neuroprotective in the nigrostriatal dopamine system. The objective of this study was to assess ghrelin levels in the early stages of PD. METHODS: Plasma was collected in the fasting state in 291 PD patients in stages 1-3 and 303 age- and sex-matched healthy controls. Additional samples were taken in the glucose response test to assess nutrition-related ghrelin levels in 20 PD patients and 20 healthy controls. The enzyme-linked immunosorbent assay was used to measure total and active plasma ghrelin levels. RESULTS: We reported that total and active plasma ghrelin levels were decreased in PD, although there was no difference across progressive PD stages. Postprandial ghrelin suppression and preprandial peak responses were both attenuated in PD. CONCLUSIONS: Plasma ghrelin levels were decreased in PD; however, this event might be irrelevant to PD progression. Ghrelin responses to meals were also impaired in PD. © 2017 International Parkinson and Movement Disorder Society.

14 Article Nesfatin-1 protects dopaminergic neurons against MPP 2017

Shen, Xiao-Li / Song, Ning / Du, Xi-Xun / Li, Yong / Xie, Jun-Xia / Jiang, Hong. ·Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines: Physiology, Medical College of Qingdao University, Qingdao, 266071, China. ·Sci Rep · Pubmed #28106099.

ABSTRACT: Several brain-gut peptides have been reported to have a close relationship with the central dopaminergic system; one such brain-gut peptide is nesfatin-1. Nesfatin-1 is a satiety peptide that is predominantly secreted by X/A-like endocrine cells in the gastric glands, where ghrelin is also secreted. We previously reported that ghrelin exerted neuroprotective effects on nigral dopaminergic neurons, which implied a role for ghrelin in Parkinson's disease (PD). In the present study, we aim to clarify whether nesfatin-1 has similar effects on dopaminergic neurons both in vivo and in vitro. We show that nesfatin-1 attenuates the loss of nigral dopaminergic neurons in the 1-methyl-4-phenyl-1, 2,3,6-tetrahydropyridine (MPTP)-induced mouse model of PD. In addition, nesfatin-1 antagonized 1-methyl-4-phenylpyridillium ion (MPP

15 Article Preferential Heme Oxygenase-1 Activation in Striatal Astrocytes Antagonizes Dopaminergic Neuron Degeneration in MPTP-Intoxicated Mice. 2016

Xu, Xiaofeng / Song, Ning / Wang, Ranran / Jiang, Hong / Xie, Junxia. ·Collaborative Innovation Center for Brain Science, Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines: Physiology, Medical College of Qingdao University, Qingdao, 266071, China. · Shandong Provincial Collaborative Innovation Center for Neurodegenerative Disorders, Qingdao, 266071, China. · Collaborative Innovation Center for Brain Science, Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines: Physiology, Medical College of Qingdao University, Qingdao, 266071, China. jxiaxie@public.qd.sd.cn. · Shandong Provincial Collaborative Innovation Center for Neurodegenerative Disorders, Qingdao, 266071, China. jxiaxie@public.qd.sd.cn. ·Mol Neurobiol · Pubmed #26385576.

ABSTRACT: Parkinson's disease (PD) is characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) accompanied by increased oxidative damage. Astrocytes, which are the most abundant glial cell types in the brain, possess higher antioxidant potential partially due to preferentially activated nuclear factor E2-related factor 2 genes. Heme oxygenase isoform 1 (HO-1) is crucial for the response to oxidative stress via the catabolism of heme to carbon monoxide, bilirubin, and iron. In the present study, we aimed to investigate astroglial expression of HO-1 in the SNpc, especially in the striatum of a subacute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-intoxicated mouse model of PD, and to investigate the neuroprotective effects of intraventricularly administrated HO-1 activator cobalt protoporphyrin IX (CoPPIX). The results showed that HO-1 was faintly distributed in neurons but not astrocytes in the normal SNpc and striatum. MPTP triggered a robust HO-1 response in the astrocytes of the striatum after 1-day treatment, but the HO-1 levels declined dramatically at day 3 and were completely undetectable at day 5. Intraventricular administration of CoPPIX for 8 days could preferentially activate HO-1 in astrocytes in the striatum but not SNpc. The content of striatal dopamine and its derivatives was restored in the subacute MPTP models. CoPPIX also increased the number of dopaminergic neurons and the tyrosine hydroxylase levels in the SNpc. These results suggest that inadequate HO-1 in striatal astrocytes might contribute to the limited antioxidant defense and dopaminergic neuron degeneration in PD, and preferential HO-1 activation in striatal astrocytes might be neuroprotective. The study thus sheds light on the targeting of HO-1 in striatal astrocytes for PD therapeutics.

16 Article Brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor inhibit ferrous iron influx via divalent metal transporter 1 and iron regulatory protein 1 regulation in ventral mesencephalic neurons. 2014

Zhang, Hao-Yun / Song, Ning / Jiang, Hong / Bi, Ming-Xia / Xie, Jun-Xia. ·Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines, Medical College of Qingdao University, Qingdao 266071, China; Shandong Provincial Collaborative Innovation Center for Neurodegenerative Disorders, PR China; Department of Histology and Embryology, Shandong Provincial Key Laboratory of Human Anatomy and Embryology, Weifang Medical University, Weifang 261053, China. · Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines, Medical College of Qingdao University, Qingdao 266071, China; Shandong Provincial Collaborative Innovation Center for Neurodegenerative Disorders, PR China. · Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines, Medical College of Qingdao University, Qingdao 266071, China; Shandong Provincial Collaborative Innovation Center for Neurodegenerative Disorders, PR China. Electronic address: jxiaxie@public.qd.sd.cn. ·Biochim Biophys Acta · Pubmed #25239763.

ABSTRACT: Iron accumulation is observed in the substantia nigra of patients with Parkinson's disease. However, it is unknown whether neurotrophic factors, brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) participate in the modulation of neuronal iron metabolism. Here, we investigated the effects and underlying mechanisms of BDNF and GDNF on the iron influx process in primary cultured ventral mesencephalic neurons. 6-hydroxydopamine-induced enhanced ferrous iron influx via improper up-regulation of divalent metal transporter 1 with iron responsive element (DMT1+IRE) was consistently relieved by BDNF and GDNF. Both the mRNA and protein levels of DMT1+IRE were down-regulated by BDNF or GDNF treatment alone. We further demonstrated the involvement of iron regulatory protein 1 (IRP1) in BDNF- and GDNF-induced DMT1+IRE expression. Extracellular-regulated kinase 1/2 (ERK1/2) and Akt were activated and participated in these processes. Inhibition of ERK1/2 and Akt phosphorylation abolished the down-regulation of IRP1 and DMT1+IRE induced by BDNF and GDNF. Taken together, these results show that BDNF and GDNF ameliorate iron accumulation via the ERK/Akt pathway, followed by inhibition of IRP1 and DMT1+IRE expression, which may provide new targets for the neuroprotective effects of these neurotrophic factors.

17 Article Depletion of canonical Wnt signaling components has a neuroprotective effect on midbrain dopaminergic neurons in an MPTP-induced mouse model of Parkinson's disease. 2014

Dai, Ting-Li / Zhang, Chan / Peng, Fang / Niu, Xue-Yuan / Hu, Ling / Zhang, Qiong / Huang, Ying / Chen, Ling / Zhang, Lei / Zhu, Weidong / Ding, Yu-Qiang / Song, Ning-Ning / Liao, Min. ·Department of Histology and Embryology, Institute of Neuroscience, Wenzhou Medical University, Wenzhou, Zhejiang 325035, P.R. China. · Key Laboratory of Arrhythmias, Ministry of Education of China, East Hospital, Tongji University School of Medicine, Shanghai 200120, P.R. China ; Department of Anatomy and Neurobiology, Tongji University School of Medicine, Shanghai 200092, P.R. China. · Key Laboratory of Arrhythmias, Ministry of Education of China, East Hospital, Tongji University School of Medicine, Shanghai 200120, P.R. China. · Department of Histology and Embryology, Institute of Neuroscience, Wenzhou Medical University, Wenzhou, Zhejiang 325035, P.R. China ; Key Laboratory of Arrhythmias, Ministry of Education of China, East Hospital, Tongji University School of Medicine, Shanghai 200120, P.R. China ; Department of Anatomy and Neurobiology, Tongji University School of Medicine, Shanghai 200092, P.R. China. ·Exp Ther Med · Pubmed #25009587.

ABSTRACT: The canonical Wnt signaling pathway is critical for the development of midbrain dopaminergic (DA) neurons, and recent studies have suggested that disruption of this signaling cascade may underlie the pathogenesis of Parkinson's disease (PD). However, the exact role of the canonical Wnt signaling pathway, including low-density lipoprotein receptor-related protein 5 and 6 (LRP5/6) and β-catenin components, in a mouse model of PD remains unclear. In the present study, the tyrosine hydroxylase (TH)-Cre transgenic mouse line was used to generate mice with the specific knockout of LRP5, LRP6 or β-catenin in DA neurons. Following inactivation of LRP5, LRP6 or β-catenin, TH-immunohistochemical staining was performed. The results indicated that β-catenin is required for the development or maintenance of these neurons; however, LRP5 and LRP6 were found to be dispensable. In 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice, the depletion of LRP5, LRP6 or β-catenin was found to be protective for the midbrain DA neurons to a certain extent. These

18 Article Role of α-synuclein aggregation and the nuclear factor E2-related factor 2/heme oxygenase-1 pathway in iron-induced neurotoxicity. 2013

He, Qing / Song, Ning / Jia, Fengjv / Xu, Huamin / Yu, Xiaojun / Xie, Junxia / Jiang, Hong. ·Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines: Physiology, Medical College of Qingdao University, Qingdao 266071, China. ·Int J Biochem Cell Biol · Pubmed #23454680.

ABSTRACT: Abnormal aggregation of α-synuclein (α-syn) plays a critical role in the pathogenesis of Parkinson's disease (PD). Iron is also believed to serve as a major contributor by inducing oxidative stress and α-syn aggregation. Here, we report that down-regulation of nuclear factor E2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) may contribute to iron-induced α-syn aggregation. In this study, we show that ferrous iron down-regulates Nrf2 and HO-1 in a time-dependent manner in SK-N-SH neuroblastoma cells. Levels of both Nrf2 and HO-1 are decreased even more by ferrous iron in SK-N-SH cells that overexpress α-syn and results in greater cell toxicity. Consistent with these results, knockdown of α-syn expression prevents reduction of Nrf2 and HO-1 by ferrous iron, eliminates α-syn aggregates, and protects SK-N-SH cells against ferrous iron-induced cell damage. Furthermore, increased HO-1 expression exerts a protective role against ferrous iron. These results support a new hypothesis of synergistic α-syn/iron cytotoxicity, whereby ferrous iron induces α-syn aggregation and neurotoxicity by inhibiting Nrf2/HO-1. Inhibition of Nrf2/HO-1 leads to more α-syn aggregation and greater toxicity induced by iron, creating a vicious cycle of iron accumulation, α-syn aggregation and HO-1 disruption in PD.

19 Article Decreased iron levels in the temporal cortex in postmortem human brains with Parkinson disease. 2013

Yu, Xiaojun / Du, Tingting / Song, Ning / He, Qing / Shen, Yong / Jiang, Hong / Xie, Junxia. ·Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines, Physiology, Medical College of Qingdao University, Qingdao, China. ·Neurology · Pubmed #23303856.

ABSTRACT: OBJECTIVE: The present study aimed to evaluate alterations in the levels of iron, divalent metal transporter 1 (DMT1) with the iron-responsive element (IRE), transferrin receptor 1 (TfR1), ferroportin 1 (FPN1), and iron regulatory protein 1 (IRP1) in the temporal cortex of human brains with Parkinson disease (PD). METHODS: Iron content was measured using an ICP-MS 7500CE detector. IRP1, DMT1+IRE, TfR1, and FPN1 expressions were determined by Western blotting. RESULTS: Iron content was significantly lower in the temporal cortex of patients with PD when compared with age-matched healthy controls. Unexpectedly, the levels of DMT1+IRE, TfR1, FPN1, and IRP1 were decreased in the temporal cortex in PD brains. No changes were observed in the temporal cortex of postmortem Alzheimer disease brains. CONCLUSIONS: Iron deprivation and iron-related protein dysregulation suggest that a different iron regulatory mechanism may exist, and that iron redistribution may occur between the temporal cortex and the substantia nigra of patients with PD.

20 Article DMT1 polymorphism and risk of Parkinson's disease. 2011

He, Qing / Du, Tingting / Yu, Xiaojun / Xie, Anmu / Song, Ning / Kang, Qi / Yu, Jintai / Tan, Lan / Xie, Junxia / Jiang, Hong. ·Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines: Physiology, Medical College of Qingdao University, Qingdao 266071, China. ·Neurosci Lett · Pubmed #21777657.

ABSTRACT: Growing evidence suggests that iron accumulation in the substantia nigra (SN) is involved in the pathology of Parkinson's diseases (PD). Divalent metal transporter 1 (DMT1) is an endogenous transporter for ferrous iron, the levels of which are significantly increased in the SN in postmortem PD brains. To study the possible association of DMT1 gene with PD occurrence, one mutation (1303C/A) and two single nucleotide polymorphisms (SNPs) (1254T/C and IVS4+44C/A) in DMT1 gene were investigated in 192 PD patients in a Han Chinese population and 193 healthy controls by method of polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Direct sequencing was performed in 10% of the samples to validate the genotyping results. Our results failed to find any significant association between the tested genotypes, alleles or mutation and PD, however, a haplotype (C alleles of 1254T and IVS4+44C/A polymorphisms) occurred at greater frequencies in PD subjects compared with that of control (18.2% versus 11.4%, OR=1.72, 95% CI=1.15-2.59, P=0.01). These results suggest that CC haplotype in DMT1 gene is a possible risk factor for PD in this Han Chinese population.

21 Article Rosmarinic acid antagonized 1-methyl-4-phenylpyridinium (MPP+)-induced neurotoxicity in MES23.5 dopaminergic cells. 2010

Du, Tingting / Li, Lu / Song, Ning / Xie, Junxia / Jiang, Hong. ·Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines: Physiology, Medical College of Qingdao University, Qingdao, 266071, China. ·Int J Toxicol · Pubmed #20966113.

ABSTRACT: Rosmarinic acid (RA) is a naturally occurring polyphenolic compound found in various plant families. We previously reported that RA exerted protective effects against 6-hydroxydopamine (6-OHDA)-induced neurotoxicity through antioxidative properties. In this study, we investigated whether RA could prevent effects of 1-methyl-4-phenylpyridinium (MPP(+))-induced insult in MES23.5 dopamineric cells. 1-Methyl-4-phenylpyridinium treatment decreased cell viability and dopamine content, as well as caused apoptotic morphological changes. 1-Methyl-4-phenylpyridinium-induced mitochondrial dysfunction, indicated by inhibition of activity associated with mitochondrial respiratory chain complex I, suggested mitochondrial transmembrane potential collapse and generation of reactive oxygen species. Decreased Bcl-2/Bax ratio and caspase 3 activation were also observed. Rosmarinic acid pretreatment restored the complex I activity of the mitochondrial respiratory chain and partially reversed the other damaging effects of MPP(+). Our results indicate that RA plays a neuroprotective role by ameliorating mitochondrial dysfunction against MPP(+)-induced cell apoptosis and suggest that RA has the potential to be considered an aid for prevention of Parkinson's disease.