Molecular neurobiologyAug 7, 2020

Lower Levels of a Key Brain Protein in the Memory Area Linked to Thinking Problems in Huntington’s Disease Mice

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Updated Apr 4, 2026

Abstract

Reduced MEF2 protein levels in the hippocampus are observed in both exon-1 (R6/1) and full-length (Hdh) mutant huntingtin mice at the onset of cognitive dysfunction.

MEF2 protein levels are significantly lower in the hippocampus of mice with Huntington's disease compared to healthy controls.
The decrease in MEF2 is not due to transcriptional changes or sequestration in mutant huntingtin aggregates.
Reduction of MEF2 is associated with increased non-apoptotic caspase activity in primary hippocampal cultures.
Activation of MEF2 transcriptional activity using BML-210 enhances neurite growth in R6/1 primary hippocampal cultures.
BML-210 treatment improves cognitive performance in R6/1 mice when administered intraperitoneally at a dose of 150 mg/Kg/day for 4 days.
Treatment with BML-210 also activates memory-related genes and increases synaptic markers in the hippocampus of R6/1 mice.

Simplified

People suffering from Huntington's disease (HD) present cognitive deficits. Hippocampal dysfunction has been involved in the HD learning and memory impairment, but proteins leading this dysregulation are not fully characterized. Here, we studied the contribution of the family of transcription factors myocyte enhancer factor 2 (MEF2) to the HD cognitive deficits. To this aim, we first analyzed MEF2 protein levels and found that they are reduced in the hippocampus of exon-1 (R6/1) and full-length (Hdh) mutant huntingtin (mHTT) mice at the onset of cognitive dysfunction. By the analysis of MEF2 mRNA levels and mHTT-MEF2 interaction, we discarded that reduced MEF2 levels are due to changes in the transcription or sequestration in mHTT aggregates. Interestingly, we showed in R6/1 primary hippocampal cultures that reduction of MEF2 is strongly related to a basal and non-apoptotic caspase activity. To decipher the involvement of hippocampal decreased MEF2 in memory impairment, we used the BML-210 molecule that activates MEF2 transcriptional activity by the disruption MEF2-histone deacetylase class IIa interaction. BML-210 treatment increased the number and length of neurites in R6/1 primary hippocampal cultures. Importantly, this effect was prevented by transduction of lentiviral particles containing shRNA against MEF2. Then, we demonstrated that intraperitoneal administration of BML-210 (150 mg/Kg/day) for 4 days in R6/1 mice improved cognitive performance. Finally, we observed that BML-210 treatment also promoted the activation of MEF2-dependent memory-related genes and the increase of synaptic markers in the hippocampus of R6/1 mice. Our findings point out that reduced hippocampal MEF2 is an important mediator of cognitive dysfunction in HD and suggest that MEF2 slight basal activation could be a good therapeutic option. Q7/Q111

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Lower Levels of a Key Brain Protein in the Memory Area Linked to Thinking Problems in Huntington’s Disease Mice

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