Related Experiment Video
Updated: Nov 24, 2025
Studying Pre-formed Fibril Induced α-Synuclein Accumulation in Primary Embryonic Mouse Midbrain Dopamine Neurons
Published on: August 16, 2020
MOBP and HIP1 in multiple system atrophy: New α-synuclein partners in glial cytoplasmic inclusions implicated in the
Conceição Bettencourt1,2, Yasuo Miki1,3, Ignazio S Piras4
1Queen Square Brain Bank for Neurological Disorders, UCL Queen Square Institute of Neurology, London, UK.
Aims:
Multiple system atrophy (MSA) is a fatal neurodegenerative disease. Similar to Parkinson's disease (PD), MSA is an α-synucleinopathy, and its pathological hallmark consists of glial cytoplasmic inclusions (GCIs) containing α-synuclein (SNCA) in oligodendrocytes. We previously identified consistent changes in myelin-associated oligodendrocyte basic protein (MOBP) and huntingtin interacting protein 1 (HIP1) DNA methylation status in MSA. We hypothesized that if differential DNA methylation at these loci is mechanistically relevant for MSA, it should have downstream consequences on gene regulation.
Methods:
We investigated the relationship between MOBP and HIP1 DNA methylation and mRNA levels in cerebellar white matter from MSA and healthy controls. Additionally, we analysed protein expression using western blotting, immunohistochemistry and proximity ligation assays.
Results:
We found decreased MOBP mRNA levels significantly correlated with increased DNA methylation in MSA. For HIP1, we found a distinct relationship between DNA methylation and gene expression levels in MSA compared to healthy controls, suggesting this locus may be subjected to epigenetic remodelling in MSA. Although soluble protein levels for MOBP and HIP1 in cerebellar white matter were not significantly different between MSA cases and controls, we found striking differences between MSA and other neurodegenerative diseases, including PD and Huntington's disease. We also found that MOBP and HIP1 are mislocalized into the GCIs in MSA, where they appear to interact with SNCA.
Conclusions:
This study supports a role for DNA methylation in downregulation of MOBP mRNA in MSA. Most importantly, the identification of MOBP and HIP1 as new constituents of GCIs emphasizes the relevance of these two loci to the pathogenesis of MSA.
Insights
DNA methylation changes in Multiple System Atrophy (MSA) impact myelin-associated oligodendrocyte basic protein (MOBP) and huntingtin interacting protein 1 (HIP1) gene expression. These proteins are found in glial cytoplasmic inclusions, highlighting their role in MSA pathogenesis.
Area of Science:
- Neuroscience
- Epigenetics
- Molecular Biology
Background:
- Multiple system atrophy (MSA) is a fatal neurodegenerative disease characterized by alpha-synucleinopathies.
- Glial cytoplasmic inclusions (GCIs) containing alpha-synuclein (SNCA) in oligodendrocytes are a hallmark of MSA.
- Previous studies identified altered DNA methylation in MOBP and HIP1 in MSA.
Purpose of the Study:
- To investigate the mechanistic link between DNA methylation and gene regulation of MOBP and HIP1 in MSA.
- To analyze the downstream consequences of differential DNA methylation on gene and protein expression in MSA.
Main Methods:
- Analysis of MOBP and HIP1 DNA methylation and mRNA levels in cerebellar white matter from MSA and control subjects.
- Protein expression analysis using western blotting, immunohistochemistry, and proximity ligation assays.
- Comparison of protein localization and interactions within GCIs.
Main Results:
- Decreased MOBP mRNA levels correlated with increased DNA methylation in MSA.
- Distinct DNA methylation-gene expression relationship for HIP1 in MSA, suggesting epigenetic remodeling.
- MOBP and HIP1 were mislocalized to GCIs in MSA, interacting with SNCA, despite unchanged soluble protein levels.
Conclusions:
- DNA methylation plays a role in the downregulation of MOBP mRNA in MSA.
- MOBP and HIP1 are identified as novel components of GCIs, underscoring their significance in MSA pathogenesis.
