Cerebral mitochondrial electron transport chain dysfunction in multiple system atrophy and Parkinson’s disease

Foti, Sandrine C.; Hargreaves, Iain P.; Carrington, Stephanie; Kiely, Aoife P.; Houlden, Henry; Holton, Janice L.

doi:10.1038/s41598-019-42902-7

Cited by 46 publications

(30 citation statements)

References 80 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The co-methylation network analysis also revealed other pathways in MSA, including mitophagy and infection related pathways. Mitochondrial dysfunction has indeed been observed in MSA, and has been suggested as a shared disease mechanism among α-synucleinopathies [11]. Furthermore, the overrepresentation of changes in infection related pathways may point to neuroinflammation, another shared mechanism across neurodegenerative diseases [14,19,32].…”

Section: Discussionmentioning

confidence: 98%

White matter DNA methylation profiling reveals deregulation of HIP1, LMAN2, MOBP, and other loci in multiple system atrophy

et al. 2019

Self Cite

View full text Add to dashboard Cite

Multiple system atrophy (MSA) is a fatal late-onset neurodegenerative disease. Although presenting with distinct pathological hallmarks, which in MSA consist of glial cytoplasmic inclusions (GCIs) containing fibrillar α-synuclein in oligodendrocytes, both MSA and Parkinson's disease are α-synucleinopathies. Pathologically, MSA can be categorized into striatonigral degeneration (SND), olivopontocerebellar atrophy (OPCA) or mixed subtypes. Despite extensive research, the regional vulnerability of the brain to MSA pathology remains poorly understood. Genetic, epigenetic and environmental factors have been proposed to explain which brain regions are affected by MSA, and to what extent. Here, we explored for the first time epigenetic changes in post-mortem brain tissue from MSA cases. We conducted a case-control study, and profiled DNA methylation in white mater from three brain regions characterized by severe-to-mild GCIs burden in the MSA mixed subtype (cerebellum, frontal lobe and occipital lobe). Our genome-wide approach using Illumina MethylationEPIC arrays and a powerful cross-region analysis identified 157 CpG sites and 79 genomic regions where DNA methylation was significantly altered in the MSA mixed-subtype cases. HIP1, LMAN2 and MOBP were amongst the most differentially methylated loci. We replicated these findings in an independent cohort and further demonstrated that DNA methylation profiles were perturbed in MSA mixed subtype, and also to variable degrees in the other pathological subtypes (OPCA and SND). Finally, our comethylation network analysis revealed several molecular signatures (modules) significantly associated with MSA (disease status and pathological subtypes), and with neurodegeneration in the cerebellum. Importantly, the co-methylation module having the strongest association with MSA included a CpG in SNCA, the gene encoding α-synuclein. Altogether, our results provide the first evidence for DNA methylation changes contributing to the molecular processes altered in MSA, some of which are shared with other neurodegenerative diseases, and highlight potential novel routes for diagnosis and therapeutic interventions.

show abstract

Section: Discussionmentioning

confidence: 98%

White matter DNA methylation profiling reveals deregulation of HIP1, LMAN2, MOBP, and other loci in multiple system atrophy

et al. 2019

Self Cite

View full text Add to dashboard Cite

show abstract

“…However, the primary cause of muscle weakness in EAE and MS has been reported to be the result of the axonal loss in the corticospinal tract [8]. A significant increase in complex I activity was observed as early as 3 DPI in the jaw muscle, as well as at 10 DPI in the spinal cord and liver of the EAE mouse, possibly in an effort to compensate for the impairment of the other MRC enzyme complexes and maintain homeostasis in oxidative phosphorylation in the diseased state as has been observed in other disorders where a pattern of impaired and increased MRC enzyme activities has been reported [41,42].…”

Section: Discussionmentioning

confidence: 92%

“…This may also be an explanation for the observed increase in complex II/III activity at 17 DPI (**; 36.7%) in the spinal cord. However, it may also be a mechanism to increase oxidative phosphorylation capacity and compensate for its initial marked decrease at 3 DPI in this tissue [41,42].…”

Section: Discussionmentioning

confidence: 99%

Assessment of Mitochondrial Dysfunction in Experimental Autoimmune Encephalomyelitis (EAE) Models of Multiple Sclerosis

Sadeghian

Heales

et al. 2019

IJMS

View full text Add to dashboard Cite

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) that involves the autoreactive T-cell attack on axonal myelin sheath. Lesions or plaques formed as a result of repeated damage and repair mechanisms lead to impaired relay of electrical impulses along the nerve, manifesting as clinical symptoms of MS. Evidence from studies in experimental autoimmune encephalomyelitis (EAE) models of MS strongly suggests that mitochondrial dysfunction presents at the onset of disease and throughout the disease course. The aim of this study was to determine if mitochondrial dysfunction occurs before clinical symptoms arise, and whether this is confined to the CNS. EAE was induced in C57B/L6 mice, and citrate synthase and mitochondrial respiratory chain (MRC) complex I–IV activities were assayed at presymptomatic (3 or 10 days post first immunisation (3 or 10 DPI)) and asymptomatic (17 days post first immunisation (17 DPI) time-points in central nervous system (CNS; spinal cord) and peripheral (liver and jaw muscle) tissues. Samples from animals immunised with myelin oligodendrocyte glycoprotein (MOG) as EAE models were compared with control animals immunised with adjuvant (ADJ) only. Significant changes in MOG compared to control ADJ animals in MRC complex I activity occurred only at presymptomatic stages, with an increase in the spinal cord at 10 DPI (87.9%), an increase at 3 DPI (25.6%) and decrease at 10 DPI (22.3%) in the jaw muscle, and an increase in the liver at 10 DPI (71.5%). MRC complex II/III activity changes occurred at presymptomatic and the asymptomatic stages of the disease, with a decrease occurring in the spinal cord at 3 DPI (87.6%) and an increase at 17 DPI (36.7%), increase in the jaw muscle at 10 DPI (25.4%), and an increase at 3 DPI (75.2%) and decrease at 17 DPI (95.7%) in the liver. Citrate synthase activity was also significantly decreased at 10 DPI (27.3%) in the liver. No significant changes were observed in complex IV across all three tissues assayed. Our findings reveal evidence that mitochondrial dysfunction is present at the asymptomatic stages in the EAE model of MS, and that the changes in MRC enzyme activities are tissue-specific and are not confined to the CNS.

show abstract

“…Based on previous studies of the pathology of the MSA and ALS, mitochondrial dysfunction might explain the coexistence of these two diseases. 2,5 It is possible that the loss of an-…”

Section: Newly Diagnosed Amyotrophic Lateral Sclerosis In a Patient Wmentioning

confidence: 99%

Newly Diagnosed Amyotrophic Lateral Sclerosis in a Patient with Multiple-System Atrophy

2020

View full text Add to dashboard Cite

Cerebral mitochondrial electron transport chain dysfunction in multiple system atrophy and Parkinson’s disease

Cited by 46 publications

References 80 publications

White matter DNA methylation profiling reveals deregulation of HIP1, LMAN2, MOBP, and other loci in multiple system atrophy

White matter DNA methylation profiling reveals deregulation of HIP1, LMAN2, MOBP, and other loci in multiple system atrophy

Assessment of Mitochondrial Dysfunction in Experimental Autoimmune Encephalomyelitis (EAE) Models of Multiple Sclerosis

Newly Diagnosed Amyotrophic Lateral Sclerosis in a Patient with Multiple-System Atrophy

Contact Info

Product

Resources

About