Transgenic conversion of omega-6 into omega-3 fatty acids in a mouse model of Parkinson's disease

Bousquet, M.; Gue, Karl; Émond, Vincent; Julien, Pierre; Kang, Jing; Cicchetti, Francesca; Calon, Frédéric

doi:10.1194/jlr.m011692

Cited by 68 publications

(46 citation statements)

References 52 publications

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“…The concentration of dopamine and its metabolites [3,4-dihydroxyphenylacetic acid (DOPAC), 3-methoxytyramine (3-MT), and homovanillic acid (HVA)] were measured from the striatum of 20-d-old mice and mice more than 6 mo old. Sample preparation and quantification by HPLC with electrochemical detection were performed according to previously published protocols (50).…”

Section: Methodsmentioning

confidence: 99%

Lmx1a and Lmx1b regulate mitochondrial functions and survival of adult midbrain dopaminergic neurons

Doucet-Beaupré

Gilbert

Profes

et al. 2016

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

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The LIM-homeodomain transcription factors Lmx1a and Lmx1b play critical roles during the development of midbrain dopaminergic progenitors, but their functions in the adult brain remain poorly understood. We show here that sustained expression of Lmx1a and Lmx1b is required for the survival of adult midbrain dopaminergic neurons. Strikingly, inactivation of Lmx1a and Lmx1b recreates cellular features observed in Parkinson's disease. We found that Lmx1a/b control the expression of key genes involved in mitochondrial functions, and their ablation results in impaired respiratory chain activity, increased oxidative stress, and mitochondrial DNA damage. Lmx1a/b deficiency caused axonal pathology characterized by α-synuclein + inclusions, followed by a progressive loss of dopaminergic neurons. These results reveal the key role of these transcription factors beyond the early developmental stages and provide mechanistic links between mitochondrial dysfunctions, α-synuclein aggregation, and the survival of dopaminergic neurons. M idbrain dopaminergic (mDA) neurons control key functions in the mammalian brain, including voluntary movement, associative learning, and motivated behaviors. Dysfunctions of the dopaminergic (DA) system underlie a wide variety of neurological and psychiatric disorders. The progressive and rather selective degeneration of mDA neurons is one of the principal pathological features of Parkinson's disease (PD) (1). In PD, neuronal loss is accompanied by the appearance of α-synucleinenriched intraneuronal inclusions called "Lewy bodies" and "Lewy neurites." The etiologies of PD remain unsolved, but mitochondrial dysfunction emerges as a central mechanism in inherited, sporadic, and toxin-induced PD (2).Specification of the subtype identities of mDA neurons begins during embryonic development. The combinatory activation of transcription factors (TFs) and their target genes allows the progenitors to mature progressively and terminally differentiate into postmitotic neuron subtypes. Tremendous efforts have been made to describe the complex spatiotemporal expression of TFs during mDA neuronal development (see refs. 3 and 4 for reviews). After mDA neuron maturation, a large number of developmentally expressed TFs remain active throughout adulthood. Our knowledge of the functional roles of these TFs in mature neurons remains rudimentary. Accumulating evidence shows that transcription factors including the nuclear receptor related 1 protein (Nurr1), En1, Pitx3, Otx2, and Foxa2, which are recognized for their role in the early development of mDA neurons, are also required for the maintenance of phenotypic neuronal identity in the adult (5).The LIM homeodomain genes Lmx1a/b are early determinants of the fate of mDA progenitors (6), and their actions are essential at each step of DA neuronal generation (7,8). The murine Lmx1a and Lmx1b proteins are closely related and share an overall amino acid identity of 64%, with 100% identity in their homeodomain and 67% and 83% identity in each LIM domain (9). These neuron...

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Section: Methodsmentioning

confidence: 99%

Lmx1a and Lmx1b regulate mitochondrial functions and survival of adult midbrain dopaminergic neurons

Doucet-Beaupré

Gilbert

Profes

et al. 2016

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

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“…The fat-1 mouse provides a desirable model to study the effects of -3 PUFAs because it allows well-controlled studies to be performed without the interference of potential confounding factors ( 47 ). Many studies have used this model to interpret the benefi cial effects of -3 PUFAs in various experimental paradigms ( 15,16,(48)(49)(50)(51). For example, fat-1 mice exhibited increased hippocampal neurogenesis evidenced by elevated density of dendritic spines of CA1 neurons, leading to a better spatial learning performance in the Morris Water Maze compared with control the last several decades, the ratio of -6/ -3 PUFAs in the diet has changed dramatically from 1-2:1 previously to 15-20:1 presently, which leads to an increase in the intake of -6 PUFAs and a concomitant decrease in the intake of -3 PUFAs ( 30 ).…”

Section: Attenuated Microglia Activation and Astrocytes Reaction In Tmentioning

confidence: 99%

Enriched endogenous omega-3 fatty acids in mice protect against global ischemia injury

Luo

Ren

Wan

et al. 2014

Journal of Lipid Research

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“…The fat1 transgenic mice rich in endogenous n-3 PUFA have been an excellent research model for studying omega-3 fatty acids and disease (Yamashita et al 2013;Bousquet et al 2011;Kang 2007). In the present study, we generated two types of transgenic zebrafish, fat1 transgenic zebrafish and fat1 and fat2 double transgenic zebrafish, both of which were rich in endogenous n-3 PUFA.…”

Section: Discussionmentioning

confidence: 99%

Double Transgenesis of Humanized fat1 and fat2 Genes Promotes Omega-3 Polyunsaturated Fatty Acids Synthesis in a Zebrafish Model

Pang

Wang

et al. 2014

Mar Biotechnol

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Omega-3 long-chain polyunsaturated fatty acid (n-3 LC-PUFA), especially eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are essential nutrients for human health. However, vertebrates, including humans, have lost the abilities to synthesize EPA and DHA de novo, majorly due to the genetic absence of delta-12 desaturase and omega-3 desaturase genes. Fishes, especially those naturally growing marine fish, are major dietary source of EPA and DHA.

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Transgenic conversion of omega-6 into omega-3 fatty acids in a mouse model of Parkinson's disease

Cited by 68 publications

References 52 publications

Lmx1a and Lmx1b regulate mitochondrial functions and survival of adult midbrain dopaminergic neurons

Lmx1a and Lmx1b regulate mitochondrial functions and survival of adult midbrain dopaminergic neurons

Enriched endogenous omega-3 fatty acids in mice protect against global ischemia injury

Double Transgenesis of Humanized fat1 and fat2 Genes Promotes Omega-3 Polyunsaturated Fatty Acids Synthesis in a Zebrafish Model

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