Cerebrospinal fluid levels of coenzyme Q10 are reduced in multiple system atrophy

Compta, Yaroslau; Giraldo, Darly M.; Muñoz, Esteban; Antonelli, Francesca; Fernández, Manel; Bravo, Paloma; Soto, M. Álvarez-Mon; Cámara, Ana; Martı́, Marı́a José; Ávila, Asunción; Bayés, Àngels; Botta-Orfila, Teresa; Caballol, Núria; Calopa, Matilde; Campdelacreu, Jaume; Ezquerra, Mario; Fábregues, Oriol de; Fernández‐Santiago, Rubén; Hernández‐Vara, Jorge; Jaumà, Serge; Marchese, Domenica; Pagonabarraga, Javier; Pástor, Pau; Planellás, Lluís; Pont‐Sunyer, Claustre; Puente, Víctor; Pujol, Montserrat; Saura, Josep; Tartaglia, Gian Gaetano; Tolosa, Eduard; Valldeoriola, Francesc

doi:10.1016/j.parkreldis.2017.10.010

Cited by 33 publications

(33 citation statements)

References 26 publications

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“…Indeed, distinguishing MSA from PD can be difficult owing to PD-like features in MSA, including occasionally a transient L-dopa response in some patients. Moreover, MSA is characterized by a prognosis of a markedly shorten life span with respect to PD ( 87 , 88 ), so a high level of accuracy in the diagnosis is needed but not yet available ( 89 ).…”

Section: Discussionmentioning

confidence: 99%

Discovering the 3′ UTR-mediated regulation of alpha-synuclein

Marchese

Botta-Orfila

Cirillo

et al. 2017

Nucleic Acids Research

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Recent evidence indicates a link between Parkinson's Disease (PD) and the expression of a-synuclein (SNCA) isoforms with different 3′ untranslated regions (3′UTRs). Yet, the post-transcriptional mechanisms regulating SNCA expression are unknown. Using a large-scale in vitro /in silico screening we identified RNA-binding proteins (RBPs) that interact with SNCA 3′ UTRs. We identified two RBPs, ELAVL1 and TIAR, that bind with high affinity to the most abundant and translationally active 3′ UTR isoform (575 nt). Knockdown and overexpression experiments indicate that both ELAVL1 and TIAR positively regulate endogenous SNCA in vivo. The mechanism of regulation implies mRNA stabilization as well as enhancement of translation in the case of TIAR. We observed significant alteration of both TIAR and ELAVL1 expression in motor cortex of post-mortem brain donors and primary cultured fibroblast from patients affected by PD and Multiple System Atrophy (MSA). Moreover, trans expression quantitative trait loci (trans-eQTLs) analysis revealed that a group of single nucleotide polymorphisms (SNPs) in TIAR genomic locus influences SNCA expression in two different brain areas, nucleus accumbens and hippocampus. Our study sheds light on the 3′ UTR-mediated regulation of SNCA and its link with PD pathogenesis, thus opening up new avenues for investigation of post-transcriptional mechanisms in neurodegeneration.

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Section: Discussionmentioning

confidence: 99%

Discovering the 3′ UTR-mediated regulation of alpha-synuclein

Marchese

Botta-Orfila

Cirillo

et al. 2017

Nucleic Acids Research

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“…Our recent data demonstrated decreased levels of plasma coenzyme Q10 in patients with MSA regardless of the COQ2 genotype 22 , in alignment with a report from another research group that also demonstrated decreased levels of serum coenzyme Q10 in patients with MSA 23 . Besides, a recent study reported reduced coenzyme Q10 levels in cerebrospinal fluid of sporadic MSA patients 24 . These results indicate that decreased levels of coenzyme Q10 are a fundamental characteristic of MSA patients with or without COQ2 mutations.…”

Section: Introductionmentioning

confidence: 98%

The pathogenesis linked to coenzyme Q10 insufficiency in iPSC-derived neurons from patients with multiple-system atrophy

Nakamoto

Okamoto

Mitsui

et al. 2018

Sci Rep

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Multiple-system atrophy (MSA) is a neurodegenerative disease characterized by autonomic failure with various combinations of parkinsonism, cerebellar ataxia, and pyramidal dysfunction. We previously reported that functionally impaired variants of COQ2, which encodes an essential enzyme in the biosynthetic pathway of coenzyme Q10, are associated with MSA. Here, we report functional deficiencies in mitochondrial respiration and the antioxidative system in induced pluripotent stem cell (iPSC)-derived neurons from an MSA patient with compound heterozygous COQ2 mutations. The functional deficiencies were rescued by site-specific CRISPR/Cas9-mediated gene corrections. We also report an increase in apoptosis of iPSC-derived neurons from MSA patients. Coenzyme Q10 reduced apoptosis of neurons from the MSA patient with compound heterozygous COQ2 mutations. Our results reveal that cellular dysfunctions attributable to decreased coenzyme Q10 levels are related to neuronal death in MSA, particularly in patients with COQ2 variants, and may contribute to the development of therapy using coenzyme Q10 supplementation.

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“…However, based on pathological and molecular evidence from MSA human studies and animal models, several factors seem to be definitely associated with the disease and may serve as therapeutic targets for disease modification (Fig. 1), including the abnormal accumulation of α-syn [30][31][32][33]43,44], microglial activation and neuroinflammation [52,[54][55][56][57][58][59][60][61]89], autophagy disturbances [64][65][66][67], mitochondrial dysfunction [12,15,66,[68][69][70][71][72][73][74] and oxidative stress [76]. Yet the primary event which triggers the whole pathogenic cascade is still unknown.…”

Section: Discussionmentioning

confidence: 99%

“…Finally, MSA patients showed reduced levels of CoQ10 in cerebrospinal fluid, plasma/serum and cerebellum [68][69][70][71][72][73], which may lead to decreased electron transport in mitochondria and increased vulnerability to oxidative stress [68,69]. Recent studies with MSA fibroblast and iPSCs-derived dopaminergic neurons observed reduced CoQ10 levels and up-regulation of some CoQ10 biosynthesis enzymes in MSA patients compared to healthy controls [66,67,74].…”

Section: Other Translational Therapies For Msamentioning

confidence: 99%

“…It is thought that the neurodegenerative process underlying MSA results from the interaction of multiple factors, including the abnormal accumulation of α-syn, microglial activation and neuroinflammation, genetic polymorphisms, dysregulation of myelin lipids [62,63], disturbances of autophagy [64][65][66][67], mitochondrial [12,15,66,[68][69][70][71][72][73][74] and proteasomal dysfunction [75,76] and oxidative stress [74,76]. At present there is no cure for MSA and only mitigation of some symptoms is feasible.…”

Section: Introductionmentioning

confidence: 99%

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MSA: From basic mechanisms to experimental therapeutics

Heras‐Garvin

Stefanova

2020

Parkinsonism & Related Disorders

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Multiple system atrophy (MSA) is a rare and fatal neurodegenerative disorder characterized by rapidly progressive autonomic and motor dysfunction. Pathologically, MSA is mainly characterized by the abnormal accumulation of misfolded α-synuclein in the cytoplasm of oligodendrocytes, which plays a major role in the pathogenesis of the disease. Striatonigral degeneration and olivopontecerebellar atrophy underlie the motor syndrome, while degeneration of autonomic centers defines the autonomic failure in MSA. At present, there is no treatment that can halt or reverse its progression. However, over the last decade several studies in preclinical models and patients have helped to better understand the pathophysiological events underlying MSA. The etiology of this fatal disorder remains unclear and may be multifactorial, caused by a combination of factors which may serve as targets for novel therapeutic approaches. In this review, we summarize the current knowledge about the etiopathogenesis and neuropathology of MSA, its different preclinical models, and the main disease modifying therapies that have been used so far or that are planned for future clinical trials.

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Cerebrospinal fluid levels of coenzyme Q10 are reduced in multiple system atrophy

Cited by 33 publications

References 26 publications

Discovering the 3′ UTR-mediated regulation of alpha-synuclein

Discovering the 3′ UTR-mediated regulation of alpha-synuclein

The pathogenesis linked to coenzyme Q10 insufficiency in iPSC-derived neurons from patients with multiple-system atrophy

MSA: From basic mechanisms to experimental therapeutics

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