Céline Perier

Biomedical Research Networking Center on Neurodegenerative Diseases

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Miquel Vila

Institució Catalana de Recerca i Estudis Avançats

Benjamin Dehay

Centre National de la Recherche Scientifique

Serge Przedborski

Columbia University

Jordi Bové

Boston Children's Hospital

ÉC

Étienne C. Hirsch

Centre National de la Recherche Scientifique

Vernice Jackson‐Lewis

Columbia University Irving Medical Center

Ariadna Recasens

University of Sydney

Erwan Bézard

Centre National de la Recherche Scientifique

JÁ

José Á. Obeso

University Hospital HM Puerta del Sur

Kim Tieu

Florida International University

Cooperative Institutions

Inserm

236

Centre National de la Recherche Scientifique

197

University of Michigan–Ann Arbor

170

Harvard University

138

Chinese Academy of Sciences

105

Washtenaw Community College

104

National Institutes of Health

UiT The Arctic University of Norway

Université Paris Cité

Istituti di Ricovero e Cura a Carattere Scientifico

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Complex I deficiency primes Bax-dependent neuronal apoptosis through mitochondrial oxidative damage

Proceedings of the National Academy of Sciences (2005)

Céline Perier Kim Tieu Christelle Guégan Casper Caspersen Vernice Jackson‐Lewis

Dysfunction of mitochondrial complex I is a feature of human neurodegenerative diseases such as Leber hereditary optic neuropathy and Parkinson's disease. This mitochondrial defect is associated with a recruitment of the mitochondrial-dependent apoptotic pathway in vivo . However, in isolated brain mitochondria, complex I dysfunction caused by either pharmacological or genetic means fails to directly activate this cell death pathway. Instead, deficits of complex I stimulate intramitochondrial oxidative stress, which, in turn, increase the releasable soluble pool of cytochrome c within the mitochondrial intermembrane space. Upon mitochondrial permeabilization by the cell death agonist Bax, more cytochrome c is released to the cytosol from brain mitochondria with impaired complex I activity. Given these results, we propose a model in which defects of complex I lower the threshold for activation of mitochondrial-dependent apoptosis by Bax, thereby rendering compromised neurons more prone to degenerate. This molecular scenario may have far-reaching implications for the development of effective neuroprotective therapies for these incurable illnesses.

Mitochondrial intermembrane space

Mitochondrial apoptosis-induced channel

DNAJA3

10.1073/pnas.0508215102

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Citations (304)

Two molecular pathways initiate mitochondria-dependent dopaminergic neurodegeneration in experimental Parkinson's disease

Proceedings of the National Academy of Sciences (2007)

Céline Perier Jordi Bové Du‐Chu Wu Benjamin Dehay Dong‐Kug Choi

Dysfunction of mitochondrial complex I is associated with a wide spectrum of neurodegenerative disorders, including Parkinson's disease (PD). In rodents, inhibition of complex I leads to degeneration of dopaminergic neurons of the substantia nigra pars compacta (SNpc), as seen in PD, through activation of mitochondria-dependent apoptotic molecular pathways. In this scenario, complex I blockade increases the soluble pool of cytochrome c in the mitochondrial intermembrane space through oxidative mechanisms, whereas activation of pro-cell death protein Bax is actually necessary to trigger neuronal death by permeabilizing the outer mitochondrial membrane and releasing cytochrome c into the cytosol. Activation of Bax after complex I inhibition relies on its transcriptional induction and translocation to the mitochondria. How complex I deficiency leads to Bax activation is currently unknown. Using gene-targeted mice, we show that the tumor suppressor p53 mediates Bax transcriptional induction after PD-related complex I blockade in vivo , but it does not participate in Bax mitochondrial translocation in this model, either by a transcription-independent mechanism or through the induction of BH3-only proteins Puma or Noxa. Instead, Bax mitochondrial translocation in this model relies mainly on the JNK-dependent activation of the BH3-only protein Bim. Targeting either Bax transcriptional induction or Bax mitochondrial translocation results in a marked attenuation of SNpc dopaminergic cell death caused by complex I inhibition. These results provide further insight into the pathogenesis of PD neurodegeneration and identify molecular targets of potential therapeutic significance for this disabling neurological illness.

Pars compacta

Mitochondrial intermembrane space

DNAJA3

10.1073/pnas.0609874104

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Citations (221)

Mitochondrial Biology and Parkinson's Disease

Cold Spring Harbor Perspectives in Medicine (2011)

Céline Perier Miquel Vila

Mitochondria are highly dynamic organelles with complex structural features which play several important cellular functions, such as the production of energy by oxidative phosphorylation, the regulation of calcium homeostasis, or the control of programmed cell death (PCD). Given its essential role in neuronal viability, alterations in mitochondrial biology can lead to neuron dysfunction and cell death. Defects in mitochondrial respiration have long been implicated in the etiology and pathogenesis of Parkinson's disease (PD). However, the role of mitochondria in PD extends well beyond defective respiration and also involves perturbations in mitochondrial dynamics, leading to alterations in mitochondrial morphology, intracellular trafficking, or quality control. Whether a primary or secondary event, mitochondrial dysfunction holds promise as a potential therapeutic target to halt the progression of dopaminergic neurodegeneration in PD.

DNAJA3

Organelle

10.1101/cshperspect.a009332

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Citations (289)

Nurr1 repression mediates cardinal features of Parkinson’s disease in α-synuclein transgenic mice

Human Molecular Genetics (2021)

Maria Argyrofthalmidou Athanasios D. Spathis Matina Maniati Amalia Poula Maira Katsianou

Duplication/triplication mutations of the SNCA locus, encoding alpha-synuclein (ASYN), and loss of function mutations in Nurr1, a nuclear receptor guiding midbrain dopaminergic neuron development, are associated with familial Parkinson's disease (PD). As we age, the expression levels of these two genes in midbrain dopaminergic neurons follow opposite directions and ASYN expression increases while the expression of Nurr1 decreases. We investigated the effect of ASYN and Nurr1 age-related expression alterations in the pathogenesis of PD by coupling Nurr1 hemizygous with ASYN(s) (heterozygote) or ASYN(d) (homozygote) transgenic mice. ASYN(d)/Nurr1+/- (2-hit) mice, contrary to the individual genetic traits, developed phenotypes consistent with dopaminergic dysfunction. Aging '2-hit' mice manifested kyphosis, severe rigid paralysis, L-DOPA responsive movement impairment and cachexia and died prematurely. Pathological abnormalities of phenotypic mice included SN neuron degeneration, extensive neuroinflammation and enhanced ASYN aggregation. Mice with two wt Nurr1 alleles [ASYN(d)/Nurr1+/+] or with reduced ASYN load [ASYN(s)/Nurr1+/-] did not develop the phenotype or pathology. Critically, we found that aging ASYN(d), in contrast to ASYN(s), mice suppress Nurr1-protein levels in a brain region-specific manner, which in addition to Nurr1 hemizygosity is necessary to instigate PD pathogenesis. Our experiments demonstrate that ASYN-dependent PD-related pathophysiology is mediated at least in part by Nurr1 down-regulation.

Pathogenesis

10.1093/hmg/ddab118

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Citations (16)

Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition)

Carolina Digital Repository (University of North Carolina at Chapel Hill) (2016)

Daniel J. Klionsky Kotb Abdelmohsen Akihisa Abe Md. Joynal Abedin Hagai Abeliovich

10.17615/12t6-p037

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Citations (3)

Increased mitochondrial function and decreased MPTP-induced dopaminergic cell death in POLG mtDNA mutator mice

Social Neuroscience (2011)

Céline Perier Andreas Bender Jordi Bové José García‐Arumí Peter Teismann

MPTP

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Behavioral Consequences of Bicuculline Injection in the Subthalamic Nucleus and the Zona Incerta in Rat

Journal of Neuroscience (2002)

Céline Perier Léon Tremblay Jean Féger Étienne C. Hirsch

The subthalamic nucleus (STN) plays a crucial role in basal ganglia functions and has been shown to be hyperactive in parkinsonian syndromes. The zona incerta (ZI), located dorsally to the STN, is also reported to be overactive after nigrostriatal denervation. In this study, we examined the behavioral consequences of an increased activity of the STN or the ZI in awake, freely moving rats. Unilateral microinjections of a GABA_A receptor antagonist (bicuculline; 25, 50, and 100 μg/μl) were performed in the STN or in the ZI of rats, and locomotor activity, spontaneous behaviors, and the occurrence of abnormal movements were quantified. Microinjection of bicuculline (50 and 100 μg/μl) into the STN did not modify spontaneous locomotor activity, whereas it induced an increase in locomotion when injected into the ZI. Furthermore, when injected into the STN or ZI, these same doses of bicuculline produced changes in spontaneous behaviors (sniffing and grooming decreased whereas chewing and rearing increased) and the appearance of abnormal movements directed contralaterally to the injection side. Application of a lower dose of bicuculline (25 ng/μl) in the STN or ZI did not modify behavior. This study suggests that the subthalamic region including the ZI, and not the STN per se, might be involved in the induction of abnormal movements. In addition, these data suggest that the hyperactivity of neurons in this region may have different consequences in the normal state and in the pathological state.

Zona incerta

Subthalamic Nucleus

GABA receptor antagonist

CNQX

10.1523/jneurosci.22-19-08711.2002

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Citations (85)

Conséquences de la dénervation dopaminergique chez la rat lésé à la 6-OHDA sur les structures situées en aval des lésions : analyse du noyau subthalamique et de la zona incerta

Céline Perier

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AMPA receptor antagonist LY293558 reverses preproenkephalin mRNA overexpression in the striatum of 6‐OHDA‐lesioned‐rats treated with l‐dopa

European Journal of Neuroscience (2002)

Céline Perier Concepció Marı́n M. Bonastre Eduardo Tolosa Étienne C. Hirsch

Abstract Striatal neurons that contain GABA and enkephalin and project to the external segment of the pallidum are thought to be overactive in Parkinson's disease. Furthermore, it has been shown that the appearance of l ‐dopa‐induced dyskinesias is correlated to an increase of preproenkephalin (PPE) mRNA expression and that some antagonists of glutamate receptors can prevent and reverse l ‐dopa‐induced dyskinesias in parkinsonian rats. The aim of this study was therefore to analyse the effect of a systemic treatment with glutamate receptor antagonists, alone or in combination with l ‐dopa, on the PPE mRNA level in rats with a 6‐hydroxydopamine‐induced unilateral lesion of the nigrostriatal pathway. In vehicle‐treated animals, PPE mRNA levels were markedly increased in the striatum on the lesioned side. Sub‐chronic l ‐dopa treatment, with bi‐daily injections for 22 days, induced a further increase in PPE mRNA expression in the denervated striatum. Administration of the AMPA receptor antagonist, LY293558, partially reversed the lesion‐induced and l ‐dopa‐induced increases in PPE mRNA expression. However, although the administration of the NMDA receptor antagonist MK801 showed a tendency to decrease this l ‐dopa induced overexpression, it did not reach significance. This study provides evidence that glutamatergic antagonists, and particularly AMPA antagonists, tend to reverse PPE neurochemical changes at the striatal level induced by l ‐dopa in hemiparkinsonian rats.

Neurochemical

Oxidopamine

10.1046/j.1460-9568.2002.02275.x

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Citations (23)

Selective neuroprotective effects of the S18Y polymorphic variant of UCH-L1 in the dopaminergic system

Human Molecular Genetics (2011)

Maria Xilouri Elli Kyratzi Pothitos M. Pitychoutis Zoi Papadopoulou-Daifoti Céline Perier

Genetic studies have implicated the neuronal ubiquitin C-terminal hydrolase (UCH) protein UCH-L1 in Parkinson's disease (PD) pathogenesis. Moreover, the function of UCH-L1 may be lost in the brains of PD and Alzheimer's disease patients. We have previously reported that the UCH-L1 polymorphic variant S18Y, potentially protective against PD in population studies, demonstrates specific antioxidant functions in cell culture. Albeit genetic, biochemical and neuropathological data support an association between UCH-L1, PD, synaptic degeneration and oxidative stress, the relationship between the dopaminergic system and UCH-L1 status remains obscure. In the current study, we have examined the dopaminergic system of mice lacking endogenous UCH-L1 protein (gracile axonal dystrophy mice). Our findings show that the lack of wild-type (WT) UCH-L1 does not influence to any significant degree the dopaminergic system at baseline or following injections of the neurotoxin methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Furthermore, using a novel intrastriatal adenoviral injection protocol, we have found that mouse nigral neurons retrogradely transduced with S18Y UCH-L1, but not the WT protein, are significantly protected against MPTP toxicity. Overall, these data provide evidence for an antioxidant and neuroprotective effect of the S18Y variant of UCH-L1, but not of the WT protein, in the dopaminergic system, and may have implications for the pathogenesis of PD or related neurodegenerative conditions, in which oxidative stress might play a role.

Neurotoxin

MPTP

Pathogenesis

10.1093/hmg/ddr521

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Citations (30)