D-serine supplement ameliorates MPP+-induced neurotoxicity via attenuating DAPK1-associated pathway in Parkinson's disease models

Abstract Background: D-serine is reported to modulate neurotransmission via regulating the activation of N-methyl-D-aspartate receptor 1 (NMDAR1) in a narrow range, and dysfunction or dysregulation of NMDAR1 contributes to the pathophysiology of Parkinson's disease (PD), a chronic and progressive neurodegenerative disorder. This study aims to further elucidate the action mechanism of D-serine/NMDAR1 in PD. Methods and Results: At animal level, we found D-Serine and NMDAR1 were cooperatively distributed in mouse brains. Compared to the control mice, a dramatic increase in D-serine content and NMDAR1 expression was revealed in striatum, whereas a significant reduction was found in cortex, hippocampus, cerebellum and brainstem in PD mice. Thus, the tissue-specific D-serine/NMDAR1 was suspected to be associated with PD. Based on the decreased levels of NMDAR1 and D-serine in the MPP+-treated glioma cells, a D-serine supplement was introduced. We found that D-serine supplement enhanced NMDAR1 expression, and triggered neuronal cells to be rescued supporting by parkinsonian parameters including morphological observation, a decreased ROS level, an increased dopamine content, and a declined acetylcholine level. Additionally, a decreased calcium, reduced DAPK1 expression, and raised Bcl2 level were found in neuronal cells supplied with D-serine. Conclusions: We speculated that D-Serine attenuated neuronal cell death via inhibiting DAPK1-related pathway. Additionally, D-serine was confirmed to display an ability to ameliorate the MPTP injury using the MPTP-administrated mice injected with D-serine. Unlike the previous description, D-serine displays a protective effect on neuronal cells. Overall, our finding highlights D-serine as a strong enhancer for NMDAR1 expression and a candidate for PD therapy. This opens up an innovative perspective for neurobiological therapy using D-serine augmentation.

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Cytokinin Plant Hormones Have Neuroprotective Activity in In Vitro Models of Parkinson’s Disease

Molecules ◽

10.3390/molecules26020361 ◽

2021 ◽

Vol 26 (2) ◽

pp. 361

Author(s):

Gabriel Gonzalez ◽

Jiří Grúz ◽

Cosimo Walter D’Acunto ◽

Petr Kaňovský ◽

Miroslav Strnad

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Cell Death ◽

Neuronal Cell Death ◽

Disease Model ◽

Neuronal Cell ◽

Zeatin Riboside ◽

Neuroprotective Activity ◽

Protective Activity

Cytokinins are adenine-based phytohormones that regulate key processes in plants, such as cell division and differentiation, root and shoot growth, apical dominance, branching, and seed germination. In preliminary studies, they have also shown protective activities against human neurodegenerative diseases. To extend knowledge of the protection (protective activity) they offer, we investigated activities of natural cytokinins against salsolinol (SAL)-induced toxicity (a Parkinson’s disease model) and glutamate (Glu)-induced death of neuron-like dopaminergic SH-SY5Y cells. We found that kinetin-3-glucoside, cis-zeatin riboside, and N6-isopentenyladenosine were active in the SAL-induced PD model. In addition, trans-, cis-zeatin, and kinetin along with the iron chelator deferoxamine (DFO) and the necroptosis inhibitor necrostatin 1 (NEC-1) significantly reduced cell death rates in the Glu-induced model. Lactate dehydrogenase assays revealed that the cytokinins provided lower neuroprotective activity than DFO and NEC-1. Moreover, they reduced apoptotic caspase-3/7 activities less strongly than DFO. However, the cytokinins had very similar effects to DFO and NEC-1 on superoxide radical production. Overall, they showed protective activity in the SAL-induced model of parkinsonian neuronal cell death and Glu-induced model of oxidative damage mainly by reduction of oxidative stress.

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Protective effects of saffron and its constituent crocetin to motor symptoms, short life span and rough-eyed phenotypes in the fly models of Parkinson’s disease in vivo

10.1101/2020.12.06.408997 ◽

2020 ◽

Author(s):

Eiji Inoue ◽

Takahiro Suzuki ◽

Yasuharu Shimizu ◽

Keiichi Sudo ◽

Haruhisa Kawasaki ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Life Span ◽

Neurodegenerative Disorder ◽

Neuronal Cell ◽

Crocus Sativus ◽

Motor Symptoms ◽

Protective Effects

AbstractParkinson’s disease (PD) is a common neurodegenerative disorder with motor symptoms linked to the loss of dopaminergic neurons in the brain. α-Synuclein is an aggregation-prone neural protein that plays a role in the pathogenesis of PD. In our previous paper, we found that saffron; the stigma of Crocus sativus Linné (Iridaceae), and its constituents (crocin and crocetin) suppressed aggregation of α-synuclein and promoted the dissociation of α-synuclein fibrils in vitro. In this study, we investigated the effect of dietary saffron and its constituent, crocetin, in vivo on a fly PD model overexpressing several mutant α-synuclein in a tissue-specific manner. Saffron and crocetin significantly suppressed the decrease of climbing ability in the Drosophila overexpressing A30P (A30P fly PD model) or G51D (G51D fly PD model) mutated α-synuclein in neurons. Saffron and crocetin extended the life span in the G51D fly PD model. Saffron suppressed the rough-eyed phenotype and the dispersion of the size histogram of the ocular long axis in A30P fly PD model in eye. Saffron had a cytoprotective effect on a human neuronal cell line with α-synuclein fibrils. These data showed that saffron and its constituent crocetin have protective effects on the progression of PD disease in animals in vivo and suggest that saffron and crocetin can be used to treat PD.

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p53-dependent neuronal cell death in a DJ-1-deficient zebrafish model of Parkinson's disease

Journal of Neurochemistry ◽

10.1111/j.1471-4159.2006.04291.x ◽

2006 ◽

Vol 0 (0) ◽

pp. 070209222715077-??? ◽

Cited By ~ 15

Author(s):

Sandrine Bretaud ◽

Claire Allen ◽

Phillip W. Ingham ◽

Oliver Bandmann

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Cell Death ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Zebrafish Model

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Neuroprotective Effects of Gagam-Sipjeondaebo-Tang, a Novel Herbal Formula, against MPTP-Induced Parkinsonian Mice and MPP+-Induced Cell Death in SH-SY5Y Cells

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2018/2420809 ◽

2018 ◽

Vol 2018 ◽

pp. 1-9 ◽

Cited By ~ 2

Author(s):

Jade Heejae Ko ◽

Ju-Hee Lee ◽

Bobin Choi ◽

Ju-Yeon Park ◽

Young-Won Kwon ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Cell Death ◽

Mitochondrial Dysfunction ◽

Apoptotic Cell ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Motor Dysfunction ◽

Herbal Formula ◽

Neuroprotective Effects

Parkinson’s disease is a neurodegenerative disease characterized by progressive cell death of dopaminergic neuron and following neurological disorders. Gagam-Sipjeondaebo-Tang (GST) is a novel herbal formula made of twelve medicinal herbs derived from Sipjeondaebo-Tang, which has been broadly used in a traditional herbal medicine. In the present study, we investigated the effects of GST against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced motor abnormalities in mice and 1-methyl-4-phenylpyridinium (MPP+)-induced neurotoxicity in SH-SY5Y cell. First, we found that GST alleviated motor dysfunction induced by MPTP, and the result showed dopaminergic neurons recovery in substantia nigra. In the cell experiment, pretreatment with GST increased the cell viability and attenuated apoptotic cell death in MPP+-treated SH-SY5Y cells. GST also inhibited reactive oxygen species production and restored the mitochondrial membrane potential loss, which were induced by MPP+. Furthermore, GST extract significantly activated ERK and Akt, cell survival-related proteins, in SH-SY5Y cells. The effect of GST preventing mitochondrial dysfunction was antagonized by pretreatment of PD98059 and LY294002, selective inhibitors of ERK and Akt, respectively. Taken together, GST alleviated abnormal motor functions and recovered neuronal cell death, mitochondrial dysfunction, possibly via ERK and Akt activation. Therefore, we suggest that GST may be a candidate for the treatment and prevention of Parkinson’s disease.

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LRRK2 links genetic and sporadic Parkinson's disease

Biochemical Society Transactions ◽

10.1042/bst20180462 ◽

2019 ◽

Vol 47 (2) ◽

pp. 651-661 ◽

Cited By ~ 41

Author(s):

Jillian H. Kluss ◽

Adamantios Mamais ◽

Mark R. Cookson

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Kinase Inhibitors ◽

Association Studies ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Vesicular Trafficking ◽

Common Mechanism ◽

Genome Wide Association Studies ◽

Functional Studies

Abstract The past two decades in research has revealed the importance of leucine-rich repeat kinase 2 (LRRK2) in both monogenic and sporadic forms of Parkinson's disease (PD). In families, mutations in LRRK2 can cause PD with age-dependent but variable penetrance and genome-wide association studies have found variants of the gene that are risk factors for sporadic PD. Functional studies have suggested that the common mechanism that links all disease-associated variants is that they increase LRRK2 kinase activity, albeit in different ways. Here, we will discuss the roles of LRRK2 in areas of inflammation and vesicular trafficking in the context of monogenic and sporadic PD. We will also provide a hypothetical model that links inflammation and vesicular trafficking together in an effort to outline how these pathways might interact and eventually lead to neuronal cell death. We will also highlight the translational potential of LRRK2-specific kinase inhibitors for the treatment of PD.

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A patient-based model of RNA mis-splicing uncovers treatment targets in Parkinson’s disease

Science Translational Medicine ◽

10.1126/scitranslmed.aau3960 ◽

2020 ◽

Vol 12 (560) ◽

pp. eaau3960

Author(s):

Ibrahim Boussaad ◽

Carolin D. Obermaier ◽

Zoé Hanss ◽

Dheeraj R. Bobbili ◽

Silvia Bolognin ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Mitochondrial Dysfunction ◽

Neurodegenerative Disorder ◽

Neuronal Cell ◽

Exon Skipping ◽

Cell Loss ◽

Genetically Engineered ◽

Neuronal Precursor Cells

Parkinson’s disease (PD) is a heterogeneous neurodegenerative disorder with monogenic forms representing prototypes of the underlying molecular pathology and reproducing to variable degrees the sporadic forms of the disease. Using a patient-based in vitro model of PARK7-linked PD, we identified a U1-dependent splicing defect causing a drastic reduction in DJ-1 protein and, consequently, mitochondrial dysfunction. Targeting defective exon skipping with genetically engineered U1-snRNA recovered DJ-1 protein expression in neuronal precursor cells and differentiated neurons. After prioritization of candidate drugs, we identified and validated a combinatorial treatment with the small-molecule compounds rectifier of aberrant splicing (RECTAS) and phenylbutyric acid, which restored DJ-1 protein and mitochondrial dysfunction in patient-derived fibroblasts as well as dopaminergic neuronal cell loss in mutant midbrain organoids. Our analysis of a large number of exomes revealed that U1 splice-site mutations were enriched in sporadic PD patients. Therefore, our study suggests an alternative strategy to restore cellular abnormalities in in vitro models of PD and provides a proof of concept for neuroprotection based on precision medicine strategies in PD.

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Amyloid aggregates of the deubiquitinase OTUB1 are neurotoxic, suggesting that they contribute to the development of Parkinson's disease

Journal of Biological Chemistry ◽

10.1074/jbc.ra119.009546 ◽

2020 ◽

Vol 295 (11) ◽

pp. 3466-3484 ◽

Cited By ~ 2

Author(s):

Raniki Kumari ◽

Roshan Kumar ◽

Sanjay Kumar ◽

Abhishek Kumar Singh ◽

Pranita Hanpude ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Neurodegenerative Disorder ◽

Neuronal Cells ◽

Lewy Bodies ◽

Cd Spectroscopy ◽

Force Microscopy ◽

Atomic Force ◽

Biochemical Assays ◽

Mammalian Cell Cultures

Parkinson's disease (PD) is a multifactorial malady and the second most common neurodegenerative disorder, characterized by loss of dopaminergic neurons in the midbrain. A hallmark of PD pathology is the formation of intracellular protein inclusions, termed Lewy bodies (LBs). Recent MS studies have shown that OTU deubiquitinase ubiquitin aldehyde-binding 1 (OTUB1), a deubiquitinating enzyme of the OTU family, is enriched together with α-synuclein in LBs from individuals with PD and is also present in amyloid plaques associated with Alzheimer's disease. In the present study, using mammalian cell cultures and a PD mouse model, along with CD spectroscopy, atomic force microscopy, immunofluorescence-based imaging, and various biochemical assays, we demonstrate that after heat-induced protein aggregation, OTUB1 reacts strongly with both anti-A11 and anti-osteocalcin antibodies, detecting oligomeric, prefibrillar structures or fibrillar species of amyloidogenic proteins, respectively. Further, recombinant OTUB1 exhibited high thioflavin-T and Congo red binding and increased β-sheet formation upon heat induction. The oligomeric OTUB1 aggregates were highly cytotoxic, characteristic of many amyloid proteins. OTUB1 formed inclusions in neuronal cells and co-localized with thioflavin S and with α-synuclein during rotenone-induced stress. It also co-localized with the disease-associated variant pS129-α-synuclein in rotenone-exposed mouse brains. Interestingly, OTUB1 aggregates were also associated with severe cytoskeleton damage, rapid internalization inside the neuronal cells, and mitochondrial damage, all of which contribute to neurotoxicity. In conclusion, the results of our study indicate that OTUB1 may contribute to LB pathology through its amyloidogenic properties.

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