ubiquinone and Multiple-System-Atrophy

To elucidate molecular bases of multiple system atrophy (MSA), we first focused on recently identified MSA multiplex families. Though linkage analyses followed by whole genome resequencing, we have identified a causative gene, COQ2, for MSA. We then conducted comprehensive nucleotide sequence analysis of COQ2 of sporadic MSA cases and controls, and found that functionally deleterious COQ2 variants confer a strong risk for developing MSA. COQ2 encodes an enzyme in the biosynthetic pathway of coenzyme Q10. Decreased synthesis of coenzyme Q10 is considered to be involved in the pathogenesis of MSA through decreased electron transport in mitochondria and increased vulnerability to oxidative stress.

Topics: Adenosine Triphosphate; Alkyl and Aryl Transferases; Electron Transport; Genetic Predisposition to Disease; Genome, Human; Genomics; Humans; Mitochondria; Multiple System Atrophy; Mutation; Oxidative Stress; Risk; Ubiquinone

Multiple system atrophy (MSA) is a neurodegenerative disease characterised by glial cytoplasmic inclusions (GCIs), containing α-synuclein. Mutated COQ2, encoding an enzyme essential for co-enzyme Q10 (CoQ10) biosynthesis, has been associated with MSA. CoQ10 is an electron carrier in the mitochondrial electron transport chain (ETC) and antioxidant. It has been shown to be deficient in MSA brain tissue, thus implicating mitochondrial dysfunction in MSA. To investigate mitochondrial dysfunction in MSA further we examined ETC activity in MSA and control brain tissue, compared with Parkinson's disease (PD) where mitochondrial dysfunction is known to be important. Using cerebellar and occipital white matter ETC complex I, II/III and IV activities were measured spectrophotometrically, selected individual components of the ETC were assessed by immunoblotting and cellular complex IV activity was analysed by enzyme histochemistry. We show decreased complex II/III activity with increased complex I and IV activity in MSA cerebellar white matter. This corresponds with the deficit in CoQ10 previously described in MSA and reflects the high regional pathological burden of GCIs. This study highlights mitochondrial dysfunction in MSA pathogenesis, suggests an influence on selective regional vulnerability to disease and points to shared disease mechanisms in α-synucleinopathies.

Topics: alpha-Synuclein; Cerebellum; Electron Transport; Humans; Immunoblotting; Inclusion Bodies; Mitochondria; Multiple System Atrophy; Parkinson Disease; Ubiquinone

Multiple-system atrophy is a neurologic disorder characterized by orthostatic hypotension, Parkinsonian signs, and cerebellar signs. Mutations in COQ2, an enzyme involved in coenzyme Q10 synthesis, were recently associated with familial and sporadic cases of multiple-system atrophy. I hypothesized that people with orthostatic hypotension with or without other symptoms of multiple-system atrophy might benefit from oral coenzyme Q10 administration.. Seven patients with symptomatic orthostatic hypotension were treated in an unrandomized manner with 257 ± 37 mg coenzyme Q10 daily for 10 ± 3 months.. Before starting coenzyme Q10, patients' systolic blood pressure fell 30 ± 4 mm Hg upon standing from a sitting position. After treatment with coenzyme Q10, their systolic blood pressure decreased 7 ± 5 mm Hg upon standing from a sitting position (P = .007 for change in systolic blood pressure decrease by paired t test).. These data suggest that orthostatic hypotension could improve with coenzyme Q10 administration and that a randomized clinical trial to test this hypothesis should be begun.

Topics: Aged; Female; Humans; Hypotension, Orthostatic; Male; Multiple System Atrophy; Treatment Outcome; Ubiquinone

The finding of mutations of the COQ2 gene and reduced coenzyme Q10 levels in the cerebellum in multiple system atrophy (MSA) suggest that coenzyme Q10 is relevant to MSA pathophysiology. Two recent studies have reported reduced coenzyme Q10 levels in plasma and serum (respectively) of MSA patients compared to Parkinson's disease and/or control subjects, but with largely overlapping values, limited comparison with other parkinsonisms, or dependence on cholesterol levels. We hypothesized that cerebrospinal fluid (CSF) is reliable to assess reductions in coenzyme Q10 as a candidate biomarker of MSA.. In this preliminary cross-sectional study we assessed CSF coenzyme Q10 levels in 20 patients with MSA from the multicenter Catalan MSA Registry and of 15 PD patients, 10 patients with progressive supranuclear palsy (PSP), and 15 control subjects from the Movement Disorders Unit Biosample Collection of Hospital Clinic de Barcelona. A specific ELISA kit was used to determine CSF coenzyme Q10 levels. CSF coenzyme Q10 levels were compared in MSA vs. the other groups globally, pair-wise, and by binary logistic regression models adjusted for age, sex, disease severity, disease duration, and dopaminergic treatment.. CSF coenzyme Q10 levels were significantly lower in MSA than in other groups in global and pair-wise comparisons, as well as in multivariate regression models. Receiver operating characteristic curve analyses yielded significant areas under the curve for MSA vs. PD, PSP and controls.. These findings support coenzyme Q10 relevance in MSA. Low CSF coenzyme Q10 levels deserve further consideration as a biomarker of MSA.

Topics: Aged; Biomarkers; Cross-Sectional Studies; Female; Humans; Male; Middle Aged; Multiple System Atrophy; Parkinson Disease; Registries; Supranuclear Palsy, Progressive; Ubiquinone

Increasing evidence supports a link between multiple system atrophy and coenzyme Q

Topics: Humans; Multiple System Atrophy; Parabens; Ubiquinone

Topics: Humans; Multiple System Atrophy; Parabens; Ubiquinone

Multiple system atrophy (MSA) is a progressive neurodegenerative disease. Recent studies revealed decreased coenzyme Q10 (COQ10) levels in the cerebellum and blood samples of MSA patients. But few studies focused on the associations of COQ10 with the clinical symptoms of MSA. In this study, we aimed to quantify plasma COQ10 and characterize its association with clinical features.. We recruited 40 patients with MSA, 30 patients with Parkinson's disease (PD), and 30 healthy participants. Plasma COQ10 was quantified by UPLC-MS. The basic demographic data, motor symptoms, and non-motor symptoms were also assessed.. Plasma COQ10 levels were significantly different in MSA, PD, and controls (P = 0.001). Post-hoc analysis revealed plasma COQ10 levels in MSA patients were lower than that in controls after adjusting for age, gender, and total cholesterol (P = 0.001). COQ10 levels differentiated MSA patients from controls with modest accuracy (P = 0.001). A sensitivity of 40% and a specificity of 97.5% was calculated with the receiver operating characteristic curve. However, COQ 10 levels did not discriminate between the MSA and PD groups (P = 0.07). Plasma COQ10 levels were correlated with the severity of motor symptoms only in MSA-C patients (b = -0.025, P = 0.009).. The association between decreased COQ10 levels and the severity of motor symptoms in MSA-C patients promotes further research. Plasma COQ10 levels alone may not be a reliable MSA diagnostic biomarker, and cannot be considered a useful biomarker in the differential diagnosis of MSA vs PD.

Topics: Aged; Biomarkers; Female; Humans; Male; Middle Aged; Multiple System Atrophy; Sensitivity and Specificity; Ubiquinone

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.

Topics: Adult; Alkyl and Aryl Transferases; Amino Acid Sequence; Atrophy; Base Sequence; Female; Humans; Induced Pluripotent Stem Cells; Male; Middle Aged; Mitochondria; Multiple System Atrophy; Mutation; Neurons; Ubiquinone

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.

Topics: Autophagy; Cells, Cultured; DNA, Mitochondrial; Electron Transport Complex II; Female; Fibroblasts; Humans; Male; Membrane Potential, Mitochondrial; Mitochondria; Mitophagy; Multiple System Atrophy; Ubiquinone

We report a 3-year follow-up of high-dose ubiquinol supplementation in a case of familial multiple system atrophy (MSA) with compound heterozygous nonsense (R387X) and missense (V393A) mutations in COQ2. A high-dose ubiquinol supplementation substantially increased total coenzyme Q

Topics: Follow-Up Studies; Humans; Male; Middle Aged; Multiple System Atrophy; Mutation; Ubiquinone

The COQ2 gene encodes an essential enzyme for biogenesis, coenzyme Q10 (CoQ10). Recessive mutations in this gene have recently been identified in families with multiple system atrophy (MSA). Moreover, specific heterozygous variants in the COQ2 gene have also been reported to confer susceptibility to sporadic MSA in Japanese cohorts. These findings have suggested the potential usefulness of CoQ10 as a blood-based biomarker for diagnosing MSA. This study measured serum levels of CoQ10 in 18 patients with MSA, 20 patients with Parkinson's disease and 18 control participants. Although differences in total CoQ10 (i.e., total levels of serum CoQ10 and its reduced form) among the three groups were not significant, total CoQ10 level corrected by serum cholesterol was significantly lower in the MSA group than in the Control group. Our findings suggest that serum CoQ10 can be used as a biomarker in the diagnosis of MSA and to provide supportive evidence for the hypothesis that decreased levels of CoQ10 in brain tissue lead to an increased risk of MSA.

Topics: Adult; Aged; Biomarkers; Brain; Case-Control Studies; Cholesterol; Chromatography, High Pressure Liquid; Demography; Female; Follow-Up Studies; Humans; Male; Middle Aged; Multiple System Atrophy; Parkinson Disease; Risk; Ubiquinone

The objective of this study was to evaluate whether the levels of coenzyme Q10 (CoQ10) in brain tissue of multiple system atrophy (MSA) patients differ from those in elderly controls and in patients with other neurodegenerative diseases.. Flash frozen brain tissue of a series of 20 pathologically confirmed MSA patients [9 olivopontocerebellar atrophy (OPCA) type, 6 striatonigral degeneration (SND) type, and 5 mixed type] was used for this study. Elderly controls (n = 37) as well as idiopathic Parkinson's disease (n = 7), dementia with Lewy bodies (n = 20), corticobasal degeneration (n = 15) and cerebellar ataxia (n = 18) patients were used as comparison groups. CoQ10 was measured in cerebellar and frontal cortex tissue by high performance liquid chromatography.. We detected a statistically significant decrease (by 3-5%) in the level of CoQ10 in the cerebellum of MSA cases (P = 0.001), specifically in OPCA (P = 0.001) and mixed cases (P = 0.005), when compared to controls as well as to other neurodegenerative diseases [dementia with Lewy bodies (P<0.001), idiopathic Parkinson's disease (P<0.001), corticobasal degeneration (P<0.001), and cerebellar ataxia (P = 0.001)].. Our results suggest that a perturbation in the CoQ10 biosynthetic pathway is associated with the pathogenesis of MSA but the mechanism behind this finding remains to be elucidated.

Topics: Aged; Aged, 80 and over; Aging; Cerebellum; Female; Humans; Male; Middle Aged; Multiple System Atrophy; Neurodegenerative Diseases; Ubiquinone

In familial and sporadic multiple system atrophy (MSA) patients, deficiency of coenzyme Q10 (CoQ10) has been associated with mutations in COQ2, which encodes the second enzyme in the CoQ10 biosynthetic pathway. Cerebellar ataxia is the most common presentation of CoQ10 deficiency, suggesting that the cerebellum might be selectively vulnerable to low levels of CoQ10 To investigate whether CoQ10 deficiency represents a common feature in the brains of MSA patients independent of the presence of COQ2 mutations, we studied CoQ10 levels in postmortem brains of 12 MSA, 9 Parkinson disease (PD), 9 essential tremor (ET) patients, and 12 controls. We also assessed mitochondrial respiratory chain enzyme activities, oxidative stress, mitochondrial mass, and levels of enzymes involved in CoQ biosynthesis. Our studies revealed CoQ10 deficiency in MSA cerebellum, which was associated with impaired CoQ biosynthesis and increased oxidative stress in the absence of COQ2 mutations. The levels of CoQ10 in the cerebella of ET and PD patients were comparable or higher than in controls. These findings suggest that CoQ10 deficiency may contribute to the pathogenesis of MSA. Because no disease modifying therapies are currently available, increasing CoQ10 levels by supplementation or upregulation of its biosynthesis may represent a novel treatment strategy for MSA patients.

Topics: Aged; Aged, 80 and over; Ataxia; Case-Control Studies; Cerebellum; Female; Humans; Male; Middle Aged; Mitochondrial Diseases; Multiple System Atrophy; Muscle Weakness; Oxidative Stress; Ubiquinone

Multiple system atrophy (MSA) is an intractable neurodegenerative disease characterized by autonomic failure in addition to various combinations of parkinsonism, cerebellar ataxia, and pyramidal dysfunction. It has recently been reported that functionally impaired variants of COQ2, which encodes an essential enzyme in the biosynthetic pathway of coenzyme Q10 (CoQ10), are associated with MSA. However, little is known about the role of CoQ10 in the pathogenesis of MSA.. To compare the levels of plasma CoQ10 in patients with MSA with those in age-, sex-, and COQ2 genotype-matched controls.. We enrolled 44 Japanese patients with MSA and 39 Japanese controls from September 1, 2012, to December 31, 2015. Patients with MSA were diagnosed on the basis of the second consensus criteria by at least 2 neurologists. Plasma CoQ10 levels were measured by high-performance liquid chromatography with electrochemical detection. Sanger sequencing of COQ2 was performed to determine the COQ2 genotypes. Multiple logistic regression analysis was performed to determine the association between MSA and the plasma CoQ10 level.. Plasma CoQ10 levels in patients with MSA were compared with those in controls after adjusting for age, sex, and COQ2 genotype.. Among 44 patients with MSA (mean [SD] age, 63.7 [8.3] years) and 39 controls (mean [SD] age, 60.3 [13.0] years), the mean (SD) plasma level of CoQ10 in patients with MSA was lower than that in controls (0.51 [0.22] vs 0.72 [0.42] µg/mL; P = .01) (difference between medians: -0.14; 95% CI, -0.25 to -0.03). The mean (SD) plasma levels of CoQ10 in patients with the cerebellar variant of MSA and those with the parkinsonian variant of MSA were 0.58 (0.19) and 0.49 (0.26) µg/mL, respectively. After adjusting for age, sex, and COQ2 genotype, the levels of plasma CoQ10 were significantly associated with MSA (95% CI, 0.10; range, 0.02 to 0.66) (P = .02).. Our data showed decreased levels of plasma CoQ10 in patients with MSA regardless of the COQ2 genotype, supporting a hypothesis that supplementation with CoQ10 is beneficial for patients with MSA.

Topics: Aged; Alkyl and Aryl Transferases; Case-Control Studies; Chromatography, High Pressure Liquid; Electrochemical Techniques; Female; Genotype; Humans; Japan; Male; Middle Aged; Multiple System Atrophy; Mutation; Ubiquinone

Topics: Biomarkers; Humans; Multiple System Atrophy; Ubiquinone

Topics: Humans; Multiple System Atrophy; Ubiquinone

Topics: Humans; Multiple System Atrophy; Ubiquinone

Prions are proteins that adopt alternative conformations that become self-propagating; the PrP(Sc) prion causes the rare human disorder Creutzfeldt-Jakob disease (CJD). We report here that multiple system atrophy (MSA) is caused by a different human prion composed of the α-synuclein protein. MSA is a slowly evolving disorder characterized by progressive loss of autonomic nervous system function and often signs of parkinsonism; the neuropathological hallmark of MSA is glial cytoplasmic inclusions consisting of filaments of α-synuclein. To determine whether human α-synuclein forms prions, we examined 14 human brain homogenates for transmission to cultured human embryonic kidney (HEK) cells expressing full-length, mutant human α-synuclein fused to yellow fluorescent protein (α-syn140*A53T-YFP) and TgM83(+/-) mice expressing α-synuclein (A53T). The TgM83(+/-) mice that were hemizygous for the mutant transgene did not develop spontaneous illness; in contrast, the TgM83(+/+) mice that were homozygous developed neurological dysfunction. Brain extracts from 14 MSA cases all transmitted neurodegeneration to TgM83(+/-) mice after incubation periods of ∼120 d, which was accompanied by deposition of α-synuclein within neuronal cell bodies and axons. All of the MSA extracts also induced aggregation of α-syn*A53T-YFP in cultured cells, whereas none of six Parkinson's disease (PD) extracts or a control sample did so. Our findings argue that MSA is caused by a unique strain of α-synuclein prions, which is different from the putative prions causing PD and from those causing spontaneous neurodegeneration in TgM83(+/+) mice. Remarkably, α-synuclein is the first new human prion to be identified, to our knowledge, since the discovery a half century ago that CJD was transmissible.

Topics: Aged; alpha-Synuclein; Animals; Brain; Exons; Female; HEK293 Cells; Humans; Immunohistochemistry; Male; Mice; Mice, Transgenic; Microscopy, Fluorescence; Middle Aged; Multiple System Atrophy; Neurodegenerative Diseases; Parkinsonian Disorders; Phosphorylation; Polymorphism, Single Nucleotide; Prions; Ubiquinone

p25α/tubulin polymerization promoting protein (TPPP) is an oligodendroglial protein that plays crucial roles including myelination, and the stabilization of microtubules. In multiple system atrophy (MSA), TPPP is suggested to relocate from the myelin sheath to the oligodendroglial cell body, before the formation of glial cytoplasmic inclusions (GCIs), the pathologic hallmark of MSA. However, much is left unknown about the re-distribution of TPPP in MSA. We generated new antibodies against the N- and C-terminus of TPPP, and analyzed control and MSA brains, including the brain of a familial MSA patient carrying homozygous mutations in the coenzyme Q2 gene (COQ2). In control brain tissues, TPPP was localized not only in the cytoplasmic component of the oligodendroglia including perinuclear cytoplasm and peripheral processes in the white matter, but also in the nucleus of a fraction (62.4%) of oligodendroglial cells. Immunoelectron microscopic analysis showed TPPP in the nucleus and mitochondrial membrane of normal oligodendroglia, while western blot also supported its nuclear and mitochondrial existence. In MSA, the prevalence of nuclear TPPP was 48.6% in the oligodendroglia lacking GCIs, whereas it was further decreased to 19.6% in the oligodendroglia with phosphorylated α-synuclein (pα-syn)-positive GCIs, both showing a significant decrease compared to controls (62.4%). In contrast, TPPP accumulated in the perinuclear cytoplasm where mitochondrial membrane (TOM20 and cytochrome C) and fission (DRP1) proteins were often immunoreactive. We conclude that in MSA-oligodendroglia, TPPP is reduced, not only in the peripheral cytoplasm, but also in the nucleus and relocated to the perinuclear cytoplasm.

Topics: Animals; Antibodies; Brain; Cell Nucleus; Cytoplasm; Humans; Immunohistochemistry; Male; Mice; Mice, Inbred C57BL; Mitochondria; Multiple System Atrophy; Mutation; Nerve Tissue Proteins; Oligodendroglia; Phosphorylation; Ubiquinone

Multiple-system atrophy is an intractable neurodegenerative disease characterized by autonomic failure in addition to various combinations of parkinsonism, cerebellar ataxia, and pyramidal dysfunction. Although multiple-system atrophy is widely considered to be a nongenetic disorder, we previously identified multiplex families with this disease, which indicates the involvement of genetic components.. In combination with linkage analysis, we performed whole-genome sequencing of a sample obtained from a member of a multiplex family in whom multiple-system atrophy had been diagnosed on autopsy. We also performed mutational analysis of samples from members of five other multiplex families and from a Japanese series (363 patients and two sets of controls, one of 520 persons and one of 2383 persons), a European series (223 patients and 315 controls), and a North American series (172 patients and 294 controls). On the basis of these analyses, we used a yeast complementation assay and measured enzyme activity of parahydroxybenzoate-polyprenyl transferase. This enzyme is encoded by the gene COQ2 and is essential for the biosynthesis of coenzyme Q10. Levels of coenzyme Q10 in lymphoblastoid cells and brain tissue were measured on high-performance liquid chromatography.. We identified a homozygous mutation (M78V-V343A/M78V-V343A) and compound heterozygous mutations (R337X/V343A) in COQ2 in two multiplex families. Furthermore, we found that a common variant (V343A) and multiple rare variants in COQ2, all of which are functionally impaired, are associated with sporadic multiple-system atrophy. The V343A variant was exclusively observed in the Japanese population.. Functionally impaired variants of COQ2 were associated with an increased risk of multiple-system atrophy in multiplex families and patients with sporadic disease, providing evidence of a role of impaired COQ2 activities in the pathogenesis of this disease. (Funded by the Japan Society for the Promotion of Science and others.).

Topics: Alkyl and Aryl Transferases; Brain Chemistry; Cell Line; DNA Mutational Analysis; Female; Genetic Linkage; Humans; Male; Multiple System Atrophy; Mutation; Pedigree; Ubiquinone