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Published on: September 26, 2018
Multiple system atrophy and apolipoprotein E
Kotaro Ogaki1, Yuka A Martens1, Michael G Heckman2
1Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.
Background:
Dysregulation of the specialized lipid metabolism involved in myelin synthesis and maintenance by oligodendrocytes has been associated with the unique neuropathology of MSA. We hypothesized that apolipoprotein E, which is associated with neurodegeneration, may also play a role in the pathogenesis of MSA.
Objective:
This study evaluated genetic associations of Apolipoprotein E alleles with risk of MSA and α-synuclein pathology, and also examined whether apolipoprotein E isoforms differentially affect α-synuclein uptake in a oligodendrocyte cell.
Methods:
One hundred sixty-eight pathologically confirmed MSA patients, 89 clinically diagnosed MSA patients, and 1,277 control subjects were genotyped for Apolipoprotein E. Human oligodendrocyte cell lines were incubated with α-synuclein and recombinant human apolipoprotein E, with internalized α-synuclein imaged by confocal microscopy and cells analyzed by flow cytometry.
Results:
No significant association with risk of MSA or was observed for either Apolipoprotein E ɛ2 or ɛ4. α-Synuclein burden was also not associated with Apolipoprotein E alleles in the pathologically confirmed patients. Interestingly, in our cell assays, apolipoprotein E ɛ4 significantly reduced α-synuclein uptake in the oligodendrocytic cell line.
Conclusions:
Despite differential effects of apolipoprotein E isoforms on α-synuclein uptake in a human oligodendrocytic cell, we did not observe a significant association at the Apolipoprotein E locus with risk of MSA or α-synuclein pathology. © 2018 International Parkinson and Movement Disorder Society.
Insights
Apolipoprotein E (APOE) isoforms did not show a significant association with Multiple System Atrophy (MSA) risk or alpha-synuclein pathology. However, APOE ε4 reduced alpha-synuclein uptake in oligodendrocytes in cell assays.
Area of Science:
- Neuroscience
- Genetics
- Lipid Metabolism
Background:
- Oligodendrocyte lipid metabolism dysregulation is linked to Multiple System Atrophy (MSA) neuropathology.
- Apolipoprotein E (APOE), known for its role in neurodegeneration, was investigated for its potential involvement in MSA pathogenesis.
Purpose of the Study:
- To assess genetic links between Apolipoprotein E (APOE) alleles and the risk of developing MSA.
- To investigate the association of APOE alleles with alpha-synuclein pathology in MSA patients.
- To determine if APOE isoforms differentially influence alpha-synuclein uptake in oligodendrocytes.
Main Methods:
- Genotyping of Apolipoprotein E (APOE) alleles in 168 pathologically confirmed MSA patients, 89 clinically diagnosed MSA patients, and 1,277 controls.
- Incubation of human oligodendrocyte cell lines with alpha-synuclein and recombinant human APOE.
- Confocal microscopy and flow cytometry to analyze alpha-synuclein internalization by oligodendrocytes.
Main Results:
- No significant association was found between Apolipoprotein E (APOE) ɛ2 or ɛ4 alleles and the risk of MSA.
- Alpha-synuclein burden in pathologically confirmed MSA patients was not associated with APOE alleles.
- APOE ɛ4 significantly decreased alpha-synuclein uptake in the studied oligodendrocyte cell line.
Conclusions:
- While APOE isoforms exhibit differential effects on alpha-synuclein uptake in oligodendrocytes, no significant genetic association was observed between the APOE locus and MSA risk or alpha-synuclein pathology.
- The study did not find a direct genetic link between APOE and MSA risk or pathology, despite in vitro findings.
- Further research may be needed to elucidate the complex role of APOE in MSA pathogenesis.
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