Coenzyme Q10 as a Peripheral Biomarker for Multiple System Atrophy

Kuo, Sheng‐Han; Quinzii, Catarina M.

doi:10.1001/jamaneurol.2016.1810

Cited by 7 publications

(7 citation statements)

References 14 publications

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“…A notable example is represented by α-syn immunotherapy (both passive and active immunization), which has shown promising results in preclinical models of synucleinopathies [4, 31, 67–69, 118] and is now under investigation in clinical trials. However, other pharmacological compounds which are not directly related to α-syn, but to independent pathogenic mechanisms, including inflammation [111, 124] and mitochondrial dysfunction [59], are under investigation.…”

Section: Discussionmentioning

confidence: 99%

“…The assessment of the activity level of respiratory chain complexes I + III and II + III in brain samples has not provided significant results, whereas the amount of the CoQ10 biosynthesis enzymes PDSS1 and COQ5 has been found to be reduced in patients’ brains. A reduction of CoQ10 level has also been described in patients’ cerebrospinal fluid [19] and plasma/serum [52, 59, 73].…”

Section: Mitochondriamentioning

confidence: 99%

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Understanding the pathogenesis of multiple system atrophy: state of the art and future perspectives

Compagnoni

Fonzo

2019

acta neuropathol commun

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Multiple System Atrophy (MSA) is a severe neurodegenerative disease clinically characterized by parkinsonism, cerebellar ataxia, dysautonomia and other motor and non-motor symptoms. Although several efforts have been dedicated to understanding the causative mechanisms of the disease, MSA pathogenesis remains widely unknown. The aim of the present review is to describe the state of the art about MSA pathogenesis, with a particular focus on alpha-synuclein accumulation and mitochondrial dysfunction, and to highlight future possible perspectives in this field. In particular, this review describes the most widely investigated hypotheses explaining alpha-synuclein accumulation in oligodendrocytes, including SNCA expression, neuron-oligodendrocyte protein transfer, impaired protein degradation and alpha-synuclein spread mechanisms. Afterwards, several recent achievements in MSA research involving mitochondrial biology are described, including the role of COQ2 mutations, Coenzyme Q10 reduction, respiratory chain dysfunction and altered mitochondrial mass. Some hints are provided about alternative pathogenic mechanisms, including inflammation and impaired autophagy. Finally, all these findings are discussed from a comprehensive point of view, putative explanations are provided and new research perspectives are suggested. Overall, the present review provides a comprehensive and up-to-date overview of the mechanisms underlying MSA pathogenesis.

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Section: Discussionmentioning

confidence: 99%

Section: Mitochondriamentioning

confidence: 99%

Understanding the pathogenesis of multiple system atrophy: state of the art and future perspectives

Compagnoni

Fonzo

2019

acta neuropathol commun

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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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Mitochondrial dysfunction in fibroblasts of Multiple System Atrophy

Compagnoni

Kleiner

Bordoni

et al. 2018

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Multiple System Atrophy is a severe neurodegenerative disorder which is characterized by a variable clinical presentation and a broad neuropathological spectrum. The pathogenic mechanisms are almost completely unknown. In the present study, we established a cellular model of MSA by using fibroblasts' primary cultures and performed several experiments to investigate the causative mechanisms of the disease, with a particular focus on mitochondrial functioning. Fibroblasts' analyses (7 MSA-P, 7 MSA-C and 6 healthy controls) displayed several anomalies in patients: an impairment of respiratory chain activity, in particular for succinate Coenzyme Q reductase (p < 0.05), and a reduction of complex II steady-state level (p < 0.01); a reduction of Coenzyme Q10 level (p < 0.001) and an up-regulation of some CoQ10 biosynthesis enzymes, namely COQ5 and COQ7; an impairment of mitophagy, demonstrated by a decreased reduction of mitochondrial markers after mitochondrial inner membrane depolarization (p < 0.05); a reduced basal autophagic activity, shown by a decreased level of LC3 II (p < 0.05); an increased mitochondrial mass in MSA-C, demonstrated by higher TOMM20 levels (p < 0.05) and suggested by a wide analysis of mitochondrial DNA content in blood of large cohorts of patients. The present study contributes to understand the causative mechanisms of Multiple System Atrophy. In particular, the observed impairment of respiratory chain activity, mitophagy and Coenzyme Q10 biosynthesis suggests that mitochondrial dysfunction plays a crucial role in the pathogenesis of the disease. Furthermore, these findings will hopefully contribute to identify novel therapeutic targets for this still incurable disorder.

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Coenzyme Q10 as a Peripheral Biomarker for Multiple System Atrophy

Cited by 7 publications

References 14 publications

Understanding the pathogenesis of multiple system atrophy: state of the art and future perspectives

Understanding the pathogenesis of multiple system atrophy: state of the art and future perspectives

MSA: From basic mechanisms to experimental therapeutics

Mitochondrial dysfunction in fibroblasts of Multiple System Atrophy

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