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Updated: May 10, 2025
Analyzing the Parkinson's Disease Mouse Model Induced by Adeno-associated Viral Vectors Encoding Human α-Synuclein
Published on: July 29, 2022
Pathological α-synuclein dysregulates epitranscriptomic writer METTL3 to drive neuroinflammation in microglia
Cameron Miller1, Alyssa Ealy2, Amanda Gregory3
1Isakson Center for Neurological Disease Research, The University of Georgia, Athens, GA 30602, USA; Department of Biochemistry and Molecular Biology, The University of Georgia, Athens, GA 30602, USA.
Abstract:
Recent reports suggest dysregulation of the N6-methyladenosine (m6A) RNA modification may contribute to the pathology of neurodegenerative diseases. Herein, we show the m6A methyltransferase complex including METTL3-the catalytic component of the nuclear-localized complex-is robustly upregulated in human microglia and astrocytes exposed to αSynf and Mn. Subcellular localization studies reveal METTL3 was predominantly cytoplasmic following Mn insult but remained nuclear following αSynf stimulation in activated microglia. Functional analysis revealed METTL3 and downstream m6A readers, including YTHDF2 and IGF2BP1-3, may regulate the proinflammatory secretome of activated microglia. Notably, methyltransferase activity and m6A abundance were significantly increased following Mn and αSynf treatment. METTL3 in Mn and αSynfin vivo models of neuroinflammation, along with human postmortem tissues from Alzheimer's disease (AD), Parkinson's disease (PD), and dementia with Lewy bodies (DLB) patients, was significantly upregulated. This was further confirmed by single-cell RNA sequencing (scRNA-seq) analysis. Overall, we demonstrate the m6A writer METTL3 may function as a major regulator of chronic neuroinflammation in synucleinopathies.
Insights
The N6-methyladenosine (m6A) RNA modification enzyme METTL3 is upregulated in neurodegenerative diseases. METTL3 may significantly regulate chronic neuroinflammation in synucleinopathies.
Area of Science:
- Neuroscience
- Molecular Biology
- Epigenetics
Background:
- N6-methyladenosine (m6A) RNA modification dysregulation is implicated in neurodegenerative diseases.
- The role of m6A writers, particularly METTL3, in neuroinflammation remains unclear.
Purpose of the Study:
- To investigate the role of METTL3 and m6A modification in neuroinflammation associated with synucleinopathies.
- To determine METTL3's regulation of microglial proinflammatory responses.
Main Methods:
- Analysis of METTL3 expression in human microglia and astrocytes exposed to alpha-synuclein fibrils (αSynf) and manganese (Mn).
- Subcellular localization studies of METTL3.
- Functional assays examining METTL3's impact on microglial secretome.
- Assessment of m6A levels and methyltransferase activity.
- In vivo studies using Mn and αSynf models.
- Analysis of human postmortem tissues from Alzheimer's disease (AD), Parkinson's disease (PD), and dementia with Lewy bodies (DLB) patients.
- Single-cell RNA sequencing (scRNA-seq).
Main Results:
- METTL3 was significantly upregulated in human microglia and astrocytes exposed to αSynf and Mn.
- METTL3 exhibited distinct subcellular localization patterns following Mn or αSynf stimulation.
- METTL3 and m6A readers (YTHDF2, IGF2BP1-3) influenced the proinflammatory secretome of activated microglia.
- Methyltransferase activity and m6A abundance increased upon Mn and αSynf treatment.
- METTL3 was upregulated in vivo models and human AD, PD, and DLB tissues.
- scRNA-seq confirmed METTL3 upregulation.
Conclusions:
- METTL3 is a key regulator of neuroinflammation in synucleinopathies.
- METTL3 upregulation is a common feature in neurodegenerative conditions involving αSyn.
- Targeting METTL3 may offer therapeutic strategies for chronic neuroinflammation.
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