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Published on: April 13, 2017
Deciphering motor dysfunction and microglial activation in mThy1-α-synuclein mice: a comprehensive study of
Brett A McGregor1, Md Obayed Raihan1,2, Afrina Brishti1
1Department of Biomedical Sciences, University of North Dakota School of Medicine and Health Sciences, Grand Forks, ND, United States.
Introduction:
Growing recognition of microglia's role in neurodegenerative disorders has accentuated the need to characterize microglia profiles and their influence on pathogenesis. To understand changes observed in the microglial profile during the progression of synucleinopathies, microglial gene expression and DNA methylation were examined in the mThy1-α-synuclein mouse model.
Methods:
Disease progression was determined using behavioral tests evaluating locomotor deficits before DNA and RNA extraction at 7 and 10 months from isolated microglia for enzymatic methyl-sequencing and RNA-sequencing.
Results:
Pathway analysis of these changes at 7 months indicates a pro-inflammatory profile and changes in terms related to synaptic maintenance. Expression and methylation at both 7 and 10 months included terms regarding mitochondrial and metabolic stress. While behavior symptoms progressed at 10 months, we see many previously activated pathways being inhibited in microglia at a later stage, with only 8 of 53 shared pathways predicted to be directionally concordant. Despite the difference in pathway directionality, 21 of the 22 genes that were differentially expressed and annotated to differentially methylated regions at both 7 and 10 months had conserved directionality changes.
Discussion:
These results highlight a critical period in disease progression, during which the microglia respond to α-synuclein, suggesting a transition in the role of microglia from the early to late stages of the disease.
Insights
Microglia profiles shift during synucleinopathy progression. Early pro-inflammatory responses transition to inhibited pathways later, indicating a dynamic role in disease.
Area of Science:
- Neuroscience
- Immunology
- Genetics
Background:
- Microglia are crucial in neurodegenerative diseases.
- Understanding microglial changes in synucleinopathies is vital.
Purpose of the Study:
- To characterize microglial gene expression and DNA methylation during synucleinopathy progression.
- To investigate the dynamic role of microglia in alpha-synucleinopathies.
Main Methods:
- Utilized the mThy1-alpha-synuclein mouse model.
- Performed behavioral tests for disease progression.
- Conducted RNA and enzymatic methyl-sequencing on isolated microglia at 7 and 10 months.
Main Results:
- Early (7 months) microglia showed pro-inflammatory profiles and synaptic maintenance changes.
- Mitochondrial and metabolic stress pathways were consistently affected.
- Later stages (10 months) revealed pathway inhibition, with conserved gene expression and methylation directionality despite overall pathway divergence.
Conclusions:
- Microglia exhibit a critical transition in response to alpha-synuclein.
- Microglial roles dynamically change from early to late stages of synucleinopathy.
