Characterization of Recessive Parkinson Disease in a Large Multicenter Study

Lesage, Suzanne; Lunati, Ariane; Houot, Marion; Romdhan, Sawssan Ben; Clot, Fabienne; Tesson, Christelle; Arezki, Mohamed; Tranchant, Christine; Vidailhet, Marie; Guern, E. Le; Corti, Olga; Mhiri, Chokri; Lohmann, Ebba; Singleton, Andrew B.; Corvol, Jean‐Christophe; Brice, Alexis; Mangone, Graziella; Toullec, Benjamin Le; Courtin, Thomas; Larcher, Kathy; Benmahdjoub, Mustapha; Arezki, Mohammed; Bouhouche, Ahmed; Anheim, Mathieu; Roze, Emmanuel; Viallet, François; Tison, François; Broussolle, Emmanuel; Emre, Murat; Hanağası, Haşmet; Bılgıç, Başar; Djebara, Mouna Ben; Gouider, Riadh; Tazir, Mériem; Singleton, Andy

doi:10.1002/ana.25787

Cited by 43 publications

(38 citation statements)

References 20 publications

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“…As mentioned above, PRKN-linked ARPD is thought to be pathologically restricted to catecholamine producing cells of the brainstem [15,40,45,53,55]. Dopamine neurons of the S. nigra have unique biophysical properties that lead to high bioenergetic demands and the related rise in oxidative stress [23].…”

Section: Discussionmentioning

confidence: 99%

Age-associated insolubility of parkin in human midbrain is linked to redox balance and sequestration of reactive dopamine metabolites

et al. 2021

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The mechanisms by which parkin protects the adult human brain from Parkinson disease remain incompletely understood. We hypothesized that parkin cysteines participate in redox reactions and that these are reflected in its posttranslational modifications. We found that in post mortem human brain, including in the Substantia nigra, parkin is largely insoluble after age 40 years; this transition is linked to its oxidation, such as at residues Cys95 and Cys253. In mice, oxidative stress induces posttranslational modifications of parkin cysteines that lower its solubility in vivo. Similarly, oxidation of recombinant parkin by hydrogen peroxide (H2O2) promotes its insolubility and aggregate formation, and in exchange leads to the reduction of H2O2. This thiol-based redox activity is diminished by parkin point mutants, e.g., p.C431F and p.G328E. In prkn-null mice, H2O2 levels are increased under oxidative stress conditions, such as acutely by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine toxin exposure or chronically due to a second, genetic hit; H2O2 levels are also significantly increased in parkin-deficient human brain. In dopamine toxicity studies, wild-type parkin, but not disease-linked mutants, protects human dopaminergic cells, in part through lowering H2O2. Parkin also neutralizes reactive, electrophilic dopamine metabolites via adduct formation, which occurs foremost at the primate-specific residue Cys95. Further, wild-type but not p.C95A-mutant parkin augments melanin formation in vitro. By probing sections of adult, human midbrain from control individuals with epitope-mapped, monoclonal antibodies, we found specific and robust parkin reactivity that co-localizes with neuromelanin pigment, frequently within LAMP-3/CD63+ lysosomes. We conclude that oxidative modifications of parkin cysteines are associated with protective outcomes, which include the reduction of H2O2, conjugation of reactive dopamine metabolites, sequestration of radicals within insoluble aggregates, and increased melanin formation. The loss of these complementary redox effects may augment oxidative stress during ageing in dopamine-producing cells of mutant PRKN allele carriers, thereby enhancing the risk of Parkinson’s-linked neurodegeneration.

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Section: Discussionmentioning

confidence: 99%

Age-associated insolubility of parkin in human midbrain is linked to redox balance and sequestration of reactive dopamine metabolites

et al. 2021

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“…As mentioned above, PRKN-linked ARPD is pathologically restricted to catecholamine producing cells of the brainstem [3,[79][80][81][82]. Dopamine neurons of the S. nigra have unique biophysical properties that lead to high bioenergetic demands and the related rise in oxidative stress [83].…”

Section: Discussionmentioning

confidence: 99%

Age-Associated Insolubility of Parkin in Human Midbrain is Linked to Redox Balance and Sequestration of Reactive Dopamine Metabolites

Tokarew

El-Kodsi

Lengacher

et al. 2020

Preprint

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The mechanisms by which parkin protects the adult human brain from Parkinson disease remain incompletely understood. We hypothesized that parkin cysteines participate in redox reactions, which are reflected in its posttranslational modifications. We found that in human control brain, including the S. nigra, parkin is largely insoluble after age 40 years, which is linked to its oxidation, e.g., at Cys95 and Cys253. In mice, oxidative stress increases posttranslational modifications at parkin cysteines and reduces its solubility. Oxidation of recombinant parkin also promotes insolubility and aggregate formation, but in parallel, lowers hydrogen peroxide (H2O2). This thiol-based redox activity is diminished by parkin point mutants, e.g., p.C431F and p.G328E. Intriguingly, in parkin-deficient human brain H2O2 concentrations are elevated. In prkn-null mice, H2O2 levels are dysregulated under oxidative stress conditions, such as acutely by MPTP-toxin exposure or chronically due to a second genetic hit. In dopamine toxicity studies, wild-type parkin, but not disease-linked mutants, protects human dopaminergic M17 cells, in part through lowering H2O2. Parkin also neutralizes reactive, electrophilic dopamine metabolites via adduct formation, which occurs foremost at primate-specific Cys95. Further, wild-type but not p.C95A-mutant parkin augments melanin formation. In sections of normal, adult human midbrain, parkin specifically co-localizes with neuromelanin pigment, frequently within LAMP-3/CD63+ lysosomes. We conclude that oxidative modifications of parkin cysteines are associated with protective outcomes, which include the reduction of H2O2, conjugation of reactive dopamine metabolites, sequestration of radicals within insoluble aggregates, and increased melanin formation. The loss of these redox effects may augment oxidative stress in dopamine producing neurons of mutant PRKN allele carriers, thereby contributing to neurodegeneration.

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“…Therefore, it is likely that the association of both genetic and environmental factors are crucial to amplify the SNpc neuronal decline in normal aging to accelerate DA neuronal degeneration as observed in PD patients (Pang et al, 2019). Several PD-causing genes such as α-synuclein (SNCA), parkin (PARK2), Leucine-rich repeat kinase 2 (LRRK2), DJ-1 (PARK7) and PTEN-induced kinase 1 (PINK1) have been implicated in the pathogenesis of PD and have contributed to the creation of various genetic animal models (Lesage et al, 2020;Tolosa et al, 2020). Additionally, exposure to numerous environmental toxins such as pesticides and heavy metals has been known to increase the risk of PD.…”

Section: Pathogenesis Of Parkinson's Diseasementioning

confidence: 99%

MicroRNA Dysregulation in Parkinson’s Disease: A Narrative Review

et al. 2021

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Parkinson’s disease (PD) is a severely debilitating neurodegenerative disease, affecting the motor system, leading to resting tremor, cogwheel rigidity, bradykinesia, walking and gait difficulties, and postural instability. The severe loss of dopaminergic neurons in the substantia nigra pars compacta causes striatal dopamine deficiency and the presence of Lewy bodies indicates a pathological hallmark of PD. Although the current treatment of PD aims to preserve dopaminergic neurons or to replace dopamine depletion in the brain, it is notable that complete recovery from the disease is yet to be achieved. Given the complexity and multisystem effects of PD, the underlying mechanisms of PD pathogenesis are yet to be elucidated. The advancement of medical technologies has given some insights in understanding the mechanism and potential treatment of PD with a special interest in the role of microRNAs (miRNAs) to unravel the pathophysiology of PD. In PD patients, it was found that striatal brain tissue and dopaminergic neurons from the substantia nigra demonstrated dysregulated miRNAs expression profiles. Hence, dysregulation of miRNAs may contribute to the pathogenesis of PD through modulation of PD-associated gene and protein expression. This review will discuss recent findings on PD-associated miRNAs dysregulation, from the regulation of PD-associated genes, dopaminergic neuron survival, α-synuclein-induced inflammation and circulating miRNAs. The next section of this review also provides an update on the potential uses of miRNAs as diagnostic biomarkers and therapeutic tools for PD.

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Characterization of Recessive Parkinson Disease in a Large Multicenter Study

Cited by 43 publications

References 20 publications

Age-associated insolubility of parkin in human midbrain is linked to redox balance and sequestration of reactive dopamine metabolites

Age-associated insolubility of parkin in human midbrain is linked to redox balance and sequestration of reactive dopamine metabolites

Age-Associated Insolubility of Parkin in Human Midbrain is Linked to Redox Balance and Sequestration of Reactive Dopamine Metabolites

MicroRNA Dysregulation in Parkinson’s Disease: A Narrative Review

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