MOBP and HIP1 in multiple system atrophy: New α‐synuclein partners in glial cytoplasmic inclusions implicated in the disease pathogenesis

Bettencourt, Conceição; Miki, Yasuo; Piras, Ignazio S.; Silva, Rohan de; Foti, Sandrine C.; Talboom, Joshua S.; Révész, Tamás; Lashley, Tammaryn; Balázs, R.; Viré, Emmanuelle; Warner, Thomas T.; Huentelman, Matt; Holton, Janice L.

doi:10.1111/nan.12688

Cited by 12 publications

(9 citation statements)

References 54 publications

(144 reference statements)

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“…The robustness of the evidences for the existence of alphasynuclein aggregates with distinct structures and/or characteristics in different synucleinopathies is increasing [26, 52-55, 63, 65, 66]. Direct or indirect interactors of aggregated alpha-synuclein within those pathogenic deposits are also being identified [63,[67][68][69][70][71][72][73][74][75][76]. These studies and the very complex results they yield are crucial for understanding the onset and differential progression of distinct synucleinopathies.…”

Section: Discussionmentioning

confidence: 99%

Disease Mechanisms of Multiple System Atrophy: What a Parallel Between the Form of Pasta and the Alpha-Synuclein Assemblies Involved in MSA and PD Tells Us

Melki

2022

Cerebellum

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Intracellular deposits rich in aggregated alpha-synuclein that appear within the central nervous system are intimately associated to Parkinson’s disease and multiple system atrophy. While it is understandable that the aggregation of proteins, which share no primary structure identity, such as alpha-synuclein and tau protein, leads to different diseases, that of a given protein yielding distinct pathologies is counterintuitive. This short review relates molecular and mechanistic processes to the observed pathological diversity associated to alpha-synuclein aggregation.

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Section: Discussionmentioning

confidence: 99%

Disease Mechanisms of Multiple System Atrophy: What a Parallel Between the Form of Pasta and the Alpha-Synuclein Assemblies Involved in MSA and PD Tells Us

Melki

2022

Cerebellum

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“…Recent studies suggest an early translocation of ␣-synuclein to the cell nucleus [10]. Further, myelin-associated oligodendrocyte basic protein and huntingtin interacting protein 1 appear to interact with ␣-synuclein thriving pathogenic cascade of MSA [11]. Converging evidence suggests a prion-like spreading of misfolded ␣-synuclein strains as a key pathogenic event [12][13][14][15][16][17][18][19][20][21] and some authors even suggested that MSA is a prion disease [7,[22][23][24].…”

Section: Targeting α-Synucleinmentioning

confidence: 99%

Disease-Modifying Therapies for Multiple System Atrophy: Where Are We in 2022?

Sidoroff

Bower²,

Stefanova

et al. 2022

JPD

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Multiple system atrophy is a rapidly progressive and fatal neurodegenerative disorder. While numerous preclinical studies suggested efficacy of potentially disease modifying agents, none of those were proven to be effective in large-scale clinical trials. Three major strategies are currently pursued in preclinical and clinical studies attempting to slow down disease progression. These target α-synuclein, neuroinflammation, and restoration of neurotrophic support. This review provides a comprehensive overview on ongoing preclinical and clinical developments of disease modifying therapies. Furthermore, we will focus on potential shortcomings of previous studies that can be avoided to improve data quality in future studies of this rare disease.

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“…Among the most consistently differentially methylated loci, across brain regions and pathological subtypes, were CpGs mapping to MOBP , HIP1 and LMAN2 . The expression of MOBP mRNA and other myelin related genes is indeed downregulated in MSA cerebellar white matter as well as in laser captured oligodendrocytes [ 86 ], and we have shown this downregulation is likely to be driven by hypermethylation at the MOBP promoter region [ 87 ]. More interestingly, a follow‐up study of a few EWAS hits led to the discovery that MOBP and HIP1 proteins are mislocalised into the GCIs, where they interact with α‐synuclein, emphasising the relevance of these loci in MSA [ 87 ].…”

Section: What Do We Know About Brain Global or Loci‐specific Dna Modi...mentioning

confidence: 99%

“…The expression of MOBP mRNA and other myelin related genes is indeed downregulated in MSA cerebellar white matter as well as in laser captured oligodendrocytes [ 86 ], and we have shown this downregulation is likely to be driven by hypermethylation at the MOBP promoter region [ 87 ]. More interestingly, a follow‐up study of a few EWAS hits led to the discovery that MOBP and HIP1 proteins are mislocalised into the GCIs, where they interact with α‐synuclein, emphasising the relevance of these loci in MSA [ 87 ]. In our genome‐wide DNA methylation analysis [ 85 ], we also identified 45 highly correlated CpG clusters using weighted gene co‐expression network analysis (WGCNA).…”

Section: What Do We Know About Brain Global or Loci‐specific Dna Modi...mentioning

confidence: 99%

Neurodegenerative movement disorders: An epigenetics perspective and promise for the future

Murthy

Cheng

Holton

et al. 2021

Neuropathology Appl Neurobio

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Neurodegenerative movement disorders (NMDs) are age-dependent disorders that are characterised by the degeneration and loss of neurons, typically accompanied by pathological accumulation of different protein aggregates in the brain, which lead to motor symptoms. NMDs include Parkinson's disease, multiple system atrophy, progressive supranuclear palsy, and Huntington's disease, among others. Epigenetic modifications are responsible for functional gene regulation during development, adult life and ageing and have progressively been implicated in complex diseases such as cancer and more recently in neurodegenerative diseases, such as NMDs. DNA methylation is by far the most widely studied epigenetic modification and consists of the reversible addition of a methyl group to the DNA without changing the DNA sequence. Although this research field is still in its infancy in relation to NMDs, an increasing number of studies point towards a role for DNA methylation in disease processes. This review addresses recent advances in epigenetic and epigenomic research in NMDs, with a focus on human brain DNA methylation studies. We discuss the current understanding of the DNA methylation changes underlying these disorders, the potential for use of these DNA modifications in peripheral tissues as biomarkers in early disease detection, classification and progression as well as a promising role in future disease management and therapy.

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MOBP and HIP1 in multiple system atrophy: New α‐synuclein partners in glial cytoplasmic inclusions implicated in the disease pathogenesis

Abstract: This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 12 publications

References 54 publications

Disease Mechanisms of Multiple System Atrophy: What a Parallel Between the Form of Pasta and the Alpha-Synuclein Assemblies Involved in MSA and PD Tells Us

Disease Mechanisms of Multiple System Atrophy: What a Parallel Between the Form of Pasta and the Alpha-Synuclein Assemblies Involved in MSA and PD Tells Us

Disease-Modifying Therapies for Multiple System Atrophy: Where Are We in 2022?

Neurodegenerative movement disorders: An epigenetics perspective and promise for the future

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