MOBP and HIP1 in multiple system atrophy: New α-synuclein partners in glial cytoplasmic inclusions implicated in the disease pathogenesis.
Neuropathol Appl Neurobiol
; 47(5): 640-652, 2021 08.
Article
em En
| MEDLINE
| ID: mdl-33368549
ABSTRACT
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.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Neuroglia
/
Atrofia de Múltiplos Sistemas
/
Proteínas de Ligação a DNA
/
Alfa-Sinucleína
/
Proteínas da Mielina
Tipo de estudo:
Etiology_studies
Limite:
Humans
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article