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Conditioned medium from BV2 microglial cells having polyleucine specifically alters startle response in mice
Ryuji Owada1, Yohei Kakuta2, Kosuke Yoshida1
1Department of Laboratory Sciences, Gunma University Graduate School of Health Sciences, 3-39-22, Showa-Machi, Maebashi, Gunma, 371-8511, Japan.
Scientific Reports
|November 5, 2022
Summary
Repeat-associated non-AUG translation (RAN) in microglia generates polyL proteins, specifically impairing the startle response in mice. This finding highlights a targeted mechanism in polyglutamine diseases affecting neurological function.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Repeat-associated non-AUG (RAN) translation produces proteins with amino acid repeats (e.g., polyA, polyL, polyS) from disease-causing genes.
- Microglia containing aggregated polyglutamine (polyQ) proteins can harm neuron-like cells.
- The specific impact of different RAN translation products within microglia on neurological function remains unclear.
Purpose of the Study:
- To determine if specific RAN translation products in microglia differentially affect neuronal health and behavior.
- To investigate the in vitro and in vivo consequences of polyalanine (polyA), polyleucine (polyL), and polyserine (polyS) expression in microglia.
Main Methods:
- Cultured microglia-like BV2 cells were engineered to express aggregated polyA, polyS, or polyL.
- Conditioned media (CM) from these cells were used to treat differentiated PC12 cells and injected into mouse brains.
- Assessed microglial differentiation, neurite outgrowth, startle response in mice, and CD68 expression.
Main Results:
- PolyA, polyS, and polyL induced aberrant differentiation in BV2 cells.
- Microglia expressing polyS and polyL released factors that caused neurite retraction in PC12 cells.
- Only polyL-containing microglia CM significantly lowered the startle response in mice when injected into the lateral ventricle or PnC.
- PolyL expression correlated with the highest CD68 levels in BV2 cells.
Conclusions:
- Microglia expressing polyleucine (polyL) RAN products specifically impair the startle response.
- This suggests that polyL derived from polyQ disease genes in microglia may uniquely disrupt neurological function.
- Targeting polyL-specific mechanisms in microglia could offer therapeutic avenues for polyglutamine diseases.
