MPTP and DSP-4 susceptibility of substantia nigra and locus coeruleus catecholaminergic neurons in mice is independent of parkin activity

Thomas, Bobby; Coelln, Rainer von; Mandir, Allen S.; Trinkaus, Daniel B.; Farah, Mohamed H.; Lim, Kah‐Leong; Calingasan, Noel Y.; Beal, M. Flint; Dawson, Valina L.; Dawson, Ted M.

doi:10.1016/j.nbd.2006.12.021

Cited by 64 publications

(56 citation statements)

References 58 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Administration of MPTP in animals selectively induces the degeneration of the nigrostriatal dopaminergic neurons as observed in PD (22). To determine whether XIAP S-nitrosylation was increased in nigrostriatal system in mice after MPTP treatment, mice were injected with MPTP as described (7,23). After MPTP treatment, mice were killed at 2-and 48-h time points, their brains were harvested, and XIAP S-nitrosylation in the striatum was determined by the biotin switch assay.…”

Section: Xiap S-nitrosylation Is Increased In An Animal Model Of Pd Amentioning

confidence: 99%

S-nitrosylation of XIAP compromises neuronal survival in Parkinson's disease

Tsang

Lee

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

144

112

View full text Add to dashboard Cite

Inhibitors of apoptosis (IAPs) are a family of highly-conserved proteins that regulate cell survival through binding to caspases, the final executioners of apoptosis. X-linked IAP (XIAP) is the most widely expressed IAP and plays an important function in regulating cell survival. XIAP contains 3 baculoviral IAP repeats (BIRs) followed by a RING finger domain at the C terminal. The BIR domains of XIAP possess anticaspase activities, whereas the RING finger domain enables XIAP to function as an E3 ubiquitin ligase in the ubiquitin and proteasomal system. Our previous study showed that parkin, a protein that is important for the survival of dopaminergic neurons in Parkinson's disease (PD), is S-nitrosylated both in vitro and in vivo in PD patients. S-nitrosylation of parkin compromises its ubiquitin E3 ligase activity and its protective function, which suggests that nitrosative stress is an important factor in regulating neuronal survival during the pathogenesis of PD. In this study we show that XIAP is S-nitrosylated in vitro and in vivo in an animal model of PD and in PD patients. Nitric oxide modifies mainly cysteine residues within the BIR domains. In contrast to parkin, S-nitrosylation of XIAP does not affect its E3 ligase activity, but instead directly compromises its anticaspase-3 and antiapoptotic function. Our results confirm that nitrosative stress contributes to PD pathogenesis through the impairment of prosurvival proteins such as parkin and XIAP through different mechanisms, indicating that abnormal S-nitrosylation plays an important role in the process of neurodegeneration.

show abstract

Section: Xiap S-nitrosylation Is Increased In An Animal Model Of Pd Amentioning

confidence: 99%

S-nitrosylation of XIAP compromises neuronal survival in Parkinson's disease

Tsang

Lee

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

144

112

View full text Add to dashboard Cite

show abstract

“…The concentrations of biogenic amines in discrete brain regions were determined by HPLC with electrochemical detection (Thomas et al, 2007). Briefly, the tissue was weighed and sonicated in 0.2 ml of 0.1 M perchloric acid containing 0.01% EDTA and 25 g/ml 3,4-dihydroxybenzylamine (Sigma) as an internal standard.…”

Section: Methodsmentioning

confidence: 99%

Amyloid Pathology Is Associated with Progressive Monoaminergic Neurodegeneration in a Transgenic Mouse Model of Alzheimer's Disease

Liu¹,

Yoo²,

Savonenko³

et al. 2008

J. Neurosci.

179

169

View full text Add to dashboard Cite

␤-Amyloid (A␤) pathology is an essential pathogenic component in Alzheimer's disease (AD). However, the significance of A␤ pathology, including A␤ deposits/oligomers and glial reactions, to neurodegeneration is unclear. In particular, despite the A␤ neurotoxicity indicated by in vitro studies, mouse models with significant A␤ deposition lack robust and progressive loss of forebrain neurons. Such results have fueled the view that A␤ pathology is insufficient for neurodegeneration in vivo. In this study, because monoaminergic (MAergic) neurons show degenerative changes at early stages of AD, we examined whether the APPswe/PS1⌬E9 mouse model recapitulates progressive MAergic neurodegeneration occurring in AD cases. We show that the progression forebrain A␤ deposition in the APPswe/ PS1⌬E9 model is associated with progressive losses of the forebrain MAergic afferents. Significantly, axonal degeneration is associated with significant atrophy of cell bodies and eventually leads to robust loss (ϳ50%) of subcortical MAergic neurons. Degeneration of these neurons occurs without obvious local A␤ or tau pathology at the subcortical sites and precedes the onset of anxiety-associated behavior in the mice. Our results show that a transgenic mouse model of A␤ pathology develops progressive MAergic neurodegeneration occurring in AD cases.

show abstract

“…TH-immunostained sections were counterstained with thionin before dehydration and cover-slipped with cytoseal. Nissl (thionin)-stained and TH-positive neuronal counts were estimated within the substantia nigra by Stereoinvestigator software (Microbrightfield) as previously described (39). CD11b-positive microglia were quantified on images captured from three coronal sections per mouse encompassing the substantia nigra.…”

Section: Immunohistochemistry and Morphometric Analysismentioning

confidence: 99%

Targeting Nrf2-Mediated Gene Transcription by Extremely Potent Synthetic Triterpenoids Attenuate Dopaminergic Neurotoxicity in the MPTP Mouse Model of Parkinson's Disease

Kaidery

Banerjee

Yang

et al. 2013

Antioxidants & Redox Signaling

Self Cite

151

115

View full text Add to dashboard Cite

Although the etiology of Parkinson's disease (PD) remains unclear, ample empirical evidence suggests that oxidative stress is a major player in the development of PD and in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxicity. Nuclear factor E2-related factor 2 (Nrf2) is a redox-sensitive transcription factor that upregulates a battery of antioxidant response element (ARE)-driven antioxidative and cytoprotective genes that defend against oxidative stress. Aims: We evaluated whether the strategy of activation of Nrf2 and its downstream network of cytoprotective genes with small molecule synthetic triterpenoids (TP) attenuate MPTPinduced PD in mice. Results: We show that synthetic TP are thus far the most potent and direct activators of the Nrf2 pathway using a novel Neh2-luciferase reporter. They upregulate several cytoprotective genes, including those involved in glutathione biosynthesis in vitro. Oral administration of TP that were structurally modified to penetrate the brain-induced messenger RNA and protein levels for a battery of Nrf2-dependent cytoprotective genes reduced MPTP-induced oxidative stress and inflammation, and ameliorated dopaminergic neurotoxicity in mice. The neuroprotective effect of these TP against MPTP neurotoxicity was dependent on Nrf2, since treatment with TP in Nrf2 knockout mice failed to block against MPTP neurotoxicity and induce Nrf2-dependent cytoprotective genes. Innovation: Extremely potent synthetic TP that are direct activators of the Nrf2 pathway block dopaminergic neurodegeneration in the MPTP mouse model of PD. Conclusion: Our results indicate that activation of Nrf2/antioxidant response element (ARE) signaling by synthetic TP is directly associated with their neuroprotective effects against MPTP neurotoxicity and suggest that targeting the Nrf2/ARE pathway is a promising approach for therapeutic intervention in PD. Antioxid. Redox Signal. 18, 139-157.

show abstract

MPTP and DSP-4 susceptibility of substantia nigra and locus coeruleus catecholaminergic neurons in mice is independent of parkin activity

Cited by 64 publications

References 58 publications

S-nitrosylation of XIAP compromises neuronal survival in Parkinson's disease

S-nitrosylation of XIAP compromises neuronal survival in Parkinson's disease

Amyloid Pathology Is Associated with Progressive Monoaminergic Neurodegeneration in a Transgenic Mouse Model of Alzheimer's Disease

Targeting Nrf2-Mediated Gene Transcription by Extremely Potent Synthetic Triterpenoids Attenuate Dopaminergic Neurotoxicity in the MPTP Mouse Model of Parkinson's Disease

Contact Info

Product

Resources

About