Decreased Myocyte Enhancer Factor 2 Levels in the Hippocampus of Huntington’s Disease Mice Are Related to Cognitive Dysfunction
| Autor: | Jordi Alberch, Irene Solés-Tarrés, Laura Vidal-Sancho, Sara Fernández-García, Xavier Xifró |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Male
0301 basic medicine Mef2 medicine.medical_specialty animal structures Huntingtin Neurite Neuroscience (miscellaneous) Mice Transgenic Caspase 3 Hippocampal formation Hippocampus 03 medical and health sciences Cellular and Molecular Neuroscience 0302 clinical medicine Mediator Huntington's disease Memory Internal medicine Neurites medicine Animals Anilides Cognitive Dysfunction RNA Messenger Transcription factor Cells Cultured Huntingtin Protein Neuronal Plasticity MEF2 Transcription Factors business.industry musculoskeletal system medicine.disease Disease Models Animal Huntington Disease 030104 developmental biology Endocrinology Neurology Synapses embryonic structures cardiovascular system Mutant Proteins business tissues Biomarkers 030217 neurology & neurosurgery Protein Binding |
| Zdroj: | Molecular Neurobiology. 57:4549-4562 |
| ISSN: | 1559-1182 0893-7648 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full text from SpringerLink