Clinical course of the first Asian family with Parkinsonism related to SNCA triplication

Sekine, Takeshi; Kagaya, Hajime; Funayama, Manabu; Li, Yuanzhe; Yoshino, Hideaki; Tomiyama, Hiroyuki

doi:10.1002/mds.23313

Cited by 36 publications

(21 citation statements)

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“…Mutations in the α-syn gene have been identified to cause familial PD; in particular, triplication of the SNCA locus [85] was correlated with an early-onset and a rapid progressive DAergic phenotype [83], suggesting a toxic gain-of-function related to high protein levels. Consistently, α-syn-deficient mice display reduced susceptibility to environmental neurotoxins [21].…”

Section: Discussionmentioning

confidence: 99%

Environmental neurotoxic challenge of conditional alpha-synuclein transgenic mice predicts a dopaminergic olfactory-striatal interplay in early PD

et al. 2014

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The olfactory bulb (OB) is one of the first brain regions in Parkinson’s disease (PD) to contain alpha-synuclein (α-syn) inclusions, possibly associated with nonmotor symptoms. Mechanisms underlying olfactory synucleinopathy, its contribution to progressive aggregation pathology and nigrostriatal dopaminergic loss observed at later stages, remain unclear. A second hit, such as environmental toxins, is suggestive for α-syn aggregation in olfactory neurons, potentially triggering disease progression. To address the possible pathogenic role of olfactory α-syn accumulation in early PD, we exposed mice with site-specific and inducible overexpression of familial PD-linked mutant α-syn in OB neurons to a low dose of the herbicide paraquat. Here, we found that olfactory α-syn per se elicited structural and behavioral abnormalities, characteristic of an early time point in models with widespread α-syn expression, including hyperactivity and increased striatal dopaminergic marker. Suppression of α-syn reversed the dopaminergic phenotype. In contrast, paraquat treatment synergistically induced degeneration of olfactory dopaminergic cells and opposed the higher reactive phenotype. Neither neurodegeneration nor behavioral abnormalities were detected in paraquat-treated mice with suppressed α-syn expression. By increasing calpain activity, paraquat induced a pathological cascade leading to inhibition of autophagy clearance and accumulation of calpain-cleaved truncated and insoluble α-syn, recapitulating biochemical and structural changes in human PD. Thus our results underscore the primary role of proteolytic failure in aggregation pathology. In addition, we provide novel evidence that olfactory dopaminergic neurons display an increased vulnerability toward neurotoxins in dependence to presence of human α-syn, possibly mediating an olfactory-striatal dopaminergic network dysfunction in mouse models and early PD.

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Section: Discussionmentioning

confidence: 99%

Environmental neurotoxic challenge of conditional alpha-synuclein transgenic mice predicts a dopaminergic olfactory-striatal interplay in early PD

et al. 2014

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“…Furthermore, this effect would be lost with mutation of the miR-7 target sequence and in the absence of the 3′-UTR, which confirmed that repression of α-synuclein expression by miR-7 requires the 3′-UTR of the α-synuclein mRNA. It has been confirmed that miR-7 actively represses α-synuclein protein expression; on the contrary, endogenous levels of α-synuclein protein are significantly increased by using specific anti-miRNA inhibitors against miR-7 31. Further, the expression of miR-7 is decreased in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intoxicated mouse model of PD, which may contribute to the increased α-synuclein expression in this model.…”

Section: Mirnas and Sncamentioning

confidence: 97%

Advances with microRNAs in Parkinson’s disease research

Ma¹,

Wei²,

Wu³

et al. 2013

DDDT

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Abstract:Parkinson's disease (PD) is the second-most common age-dependent neurodegenerative disorder and is caused by severe degeneration of dopaminergic neurons in the substantia nigra pars compacta. Unfortunately, current treatment only targets symptoms and involves dopamine replacement therapy, which does not counteract progressive degeneration. MicroRNAs (miRNAs) are a class of small RNA molecules implicated in post-transcriptional regulation of gene expression during development. Recent studies show that miRNAs are playing an important role in the pathophysiology of PD. miRNA-based therapy is a powerful tool with which to study gene function, investigate the mechanism of the disease, and validate drug targets. In this review, we focus on the recent advances of the use of miRNAs in the pathogenesis of PD.

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“…Later, several families with different ethnic background have been described, including members carrying four copies (triplication) or three copies (duplication) of SNCA (Table 1) (Wang et al 2013; Keyser et al 2010; Sekine et al 2010; Kojovic et al 2012; Darvish et al 2013; Olgiati et al 2015; Ferese et al 2015; Uchiyama et al 2008; Ahn et al 2008; Nishioka et al 2006, 2009; Chartier-Harlin et al 2004; Ibanez et al 2004, 2009; Sironi et al 2010; Pankratz et al 2011; Elia et al 2013; Konno et al 2016; Ross et al 2008; Kara et al 2014; Mutez et al 2011). In general, triplication generates very high expression of mRNA and protein molecules and influences the clinical manifestations of PD, causing severe forms of Parkinsonism similar to dementia with Lewy body.…”

Section: Copy Number Variations In Familiar Pd Genesmentioning

confidence: 99%

Copy number variability in Parkinson’s disease: assembling the puzzle through a systems biology approach

et al. 2016

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Parkinson’s disease (PD), the second most common progressive neurodegenerative disorder of aging, was long believed to be a non-genetic sporadic origin syndrome. The proof that several genetic loci are responsible for rare Mendelian forms has represented a revolutionary breakthrough, enabling to reveal molecular mechanisms underlying this debilitating still incurable condition. While single nucleotide polymorphisms (SNPs) and small indels constitute the most commonly investigated DNA variations accounting for only a limited number of PD cases, larger genomic molecular rearrangements have emerged as significant PD-causing mutations, including submicroscopic Copy Number Variations (CNVs). CNVs constitute a prevalent source of genomic variations and substantially participate in each individual’s genomic makeup and phenotypic outcome. However, the majority of genetic studies have focused their attention on single candidate-gene mutations or on common variants reaching a significant statistical level of acceptance. This gene-centric approach is insufficient to uncover the genetic background of polygenic multifactorial disorders like PD, and potentially masks rare individual CNVs that all together might contribute to disease development or progression. In this review, we will discuss literature and bioinformatic data describing the involvement of CNVs on PD pathobiology. We will analyze the most frequent copy number changes in familiar PD genes and provide a “systems biology” overview of rare individual rearrangements that could functionally act on commonly deregulated molecular pathways. Assessing the global genome-wide burden of CNVs in PD patients may reveal new disease-related molecular mechanisms, and open the window to a new possible genetic scenario in the unsolved PD puzzle.Electronic supplementary materialThe online version of this article (doi:10.1007/s00439-016-1749-4) contains supplementary material, which is available to authorized users.

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Clinical course of the first Asian family with Parkinsonism related to SNCA triplication

Cited by 36 publications

References 10 publications

Environmental neurotoxic challenge of conditional alpha-synuclein transgenic mice predicts a dopaminergic olfactory-striatal interplay in early PD

Environmental neurotoxic challenge of conditional alpha-synuclein transgenic mice predicts a dopaminergic olfactory-striatal interplay in early PD

Advances with microRNAs in Parkinson’s disease research

Copy number variability in Parkinson’s disease: assembling the puzzle through a systems biology approach

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Clinical course of the first Asian family with Parkinsonism related to SNCA triplication

Cited by 36 publications

References 10 publications

Environmental neurotoxic challenge of conditional alpha-synuclein transgenic mice predicts a dopaminergic olfactory-striatal interplay in early PD

Environmental neurotoxic challenge of conditional alpha-synuclein transgenic mice predicts a dopaminergic olfactory-striatal interplay in early PD

Advances with microRNAs in Parkinson&rsquo;s disease research

Copy number variability in Parkinson’s disease: assembling the puzzle through a systems biology approach

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Advances with microRNAs in Parkinson’s disease research