Immunohistochemical and Molecular Investigations Show Alteration in the Inflammatory Profile of Multiple System Atrophy Brain

Kiely, Aoife P.; Murray, Christina E.; Foti, Sandrine C.; Benson, Bridget C.; Courtney, Robert J.; Strand, Catherine; Lashley, Tammaryn; Holton, Janice L.

doi:10.1093/jnen/nly035

Cited by 20 publications

(15 citation statements)

References 60 publications

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“…This finding may suggest that TGF-beta is a key regulator of the inflammatory processes that may be more generalizable to neurodegenerative diseases regardless of the underlying causes and resulting neuropathologies. In the yellow module we found also MASP1 (log2 FC = 0.944; adj p 0.380), whose mRNA expression was found upregulated in a separate study conducted using frontal lobe post-mortem brains from MSA patients and controls [29].…”

Section: The Importance Of Neuroinflammation In Msa-cmentioning

confidence: 74%

Transcriptional profiling of Multiple System Atrophy cerebellar tissue highlights differences between the parkinsonian and cerebellar sub-types of the disease

Piras

Bleul

Schrauwen

et al. 2020

Preprint

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Multiple system atrophy (MSA) is a rare adult-onset neurodegenerative disease of unknown cause, with no effective therapeutic options, and no cure. Limited work to date has attempted to characterize the transcriptional changes associated with the disease, which presents as either predominating parkinsonian (MSA-P) or cerebellar (MSC-C) symptoms. We report here the results of RNA expression profiling of cerebellar white matter (CWM) tissue from two independent cohorts of MSA patients (n=66) and healthy controls (HC; n=66). RNA samples from bulk brain tissue and from oligodendrocytes obtained by laser capture microdissection (LCM) were sequenced. Differentially expressed genes (DEGs) were obtained and were examined before and after stratifying by MSA clinical sub-type.We detected the highest number of DEGs in the MSA-C group (n = 747) while only one gene was noted in MSA-P, highlighting the larger dysregulation of the transcriptome in the MSA-C CWM. Results from both bulk tissue and LCM analysis of MSA-C showed a downregulation of oligodendrocyte genes and an enrichment for myelination processes with a key role noted for the QKI gene. Additionally, we observed a significant upregulation of neuron-specific gene expression in MSA-C and an enrichment for synaptic processes. A third cluster of genes was associated with the upregulation of astrocyte and endothelial genes, two cell types with a key role in inflammation processes. Finally, network analysis in MSA-C showed enrichment for βamyloid related functional classes, including the known Alzheimer's disease (AD) genes, APP and PSEN1. This is the largest RNA profiling study ever conducted on post-mortem brain tissue from MSA patients. We were able to define specific gene expression signatures for MSA-C highlighting the different stages of the complex neurodegenerative cascade of the disease that included alterations in several cell-specific transcriptional programs. Finally, several results suggest a common transcriptional dysregulation between MSA and ADrelated genes despite the clinical and neuropathological distinctions between the two diseases.3

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Section: The Importance Of Neuroinflammation In Msa-cmentioning

confidence: 74%

Transcriptional profiling of Multiple System Atrophy cerebellar tissue highlights differences between the parkinsonian and cerebellar sub-types of the disease

Piras

Bleul

Schrauwen

et al. 2020

Preprint

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“…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]. Interestingly, a recent study reports on the crosstalk between neuroinflammation and oligodendrocytes containing GCIs leading to an immune response locally restricted to white matter regions in MSA [15].…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2019

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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.

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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%

“…Microglial activation and neuroinflammation constitute important features of MSA according to PET and pathological studies of MSA brains [52,[54][55][56][57][58][59][60][61]. Histopathological findings in MSA showed activated microglia in the main brain areas affected by the disease, which paralleled system degeneration and was associated with the presence of α-syn inclusions [48,55,56,60,168].…”

Section: Modulating Microglial Activation and Neuroinflammation In Msamentioning

confidence: 99%

“…Moreover, the possible pathogenic role of GCIs and αsyn aggregation and accumulation has been experimentally confirmed in transgenic animal models overexpressing α-syn specifically in oligodendrocytes [43,44]. Besides the presence of GCIs, other prominent microscopic features of MSA are selective neuronal loss and axonal degeneration [45][46][47], demyelination [48][49][50], astrogliosis [38,[51][52][53], microglial activation and neuroinflammation [52,[54][55][56][57][58][59][60][61].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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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Immunohistochemical and Molecular Investigations Show Alteration in the Inflammatory Profile of Multiple System Atrophy Brain

Cited by 20 publications

References 60 publications

Transcriptional profiling of Multiple System Atrophy cerebellar tissue highlights differences between the parkinsonian and cerebellar sub-types of the disease

Transcriptional profiling of Multiple System Atrophy cerebellar tissue highlights differences between the parkinsonian and cerebellar sub-types of the disease

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

MSA: From basic mechanisms to experimental therapeutics

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