Abstract:
: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 (HdhQ7/Q111) 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.
journal_name
Mol Neurobioljournal_title
Molecular neurobiologyauthors
Vidal-Sancho L,Fernández-García S,Solés-Tarrés I,Alberch J,Xifró Xdoi
10.1007/s12035-020-02041-xsubject
Has Abstractpub_date
2020-11-01 00:00:00pages
4549-4562issue
11eissn
0893-7648issn
1559-1182pii
10.1007/s12035-020-02041-xjournal_volume
57pub_type
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