Pharmacogenetic modulation of STEP improves motor and cognitive function in a mouse model of Huntington's disease
| Autor: | Garikoitz Azkona, Esther Pérez-Navarro, Jordi Alberch, Sara Martínez-Torres, Montse Milà, Marta Garcia-Forn, Gerardo García-Díaz Barriga |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
Male
0301 basic medicine Huntingtin Excitotoxicity Striatum Protein tyrosine phosphatase Motor Activity Hippocampal formation Huntington's chorea medicine.disease_cause Hippocampus phosphoERK1/2 lcsh:RC321-571 Proteïna-tirosina-fosfatasa Mice 03 medical and health sciences Cognition 0302 clinical medicine Huntington's disease Corea de Huntington Animals Medicine Hereditary Neurodegenerative Disorder lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry Protein-tyrosine phosphatase Inhibition Mice Knockout business.industry Mutació (Biologia) Mutation (Biology) Protein Tyrosine Phosphatases Non-Receptor medicine.disease Mutant huntingtin aggregates Motor coordination DARPP-32 Mice Inbred C57BL Disease Models Animal Huntington Disease 030104 developmental biology Neurology Motor Skills Inhibició Pharmacogenetics Farmacogenètica Cognitive function business Neuroscience 030217 neurology & neurosurgery |
| Zdroj: | Neurobiology of Disease, Vol 120, Iss, Pp 88-97 (2018) Dipòsit Digital de la UB Universidad de Barcelona |
| Popis: | Huntington's disease (HD) is a hereditary neurodegenerative disorder caused by an expansion of a CAG repeat in the huntingtin (htt) gene, which results in an aberrant form of the protein (mhtt). This leads to motor and cognitive deficits associated with corticostriatal and hippocampal alterations. The levels of STriatal-Enriched protein tyrosine Phosphatase (STEP), a neural-specific tyrosine phosphatase that opposes the development of synaptic strengthening, are decreased in the striatum of HD patients and also in R6/1 mice, thereby contributing to the resistance to excitotoxicity described in this HD mouse model. Here, we aimed to analyze whether STEP inactivation plays a role in the pathophysiology of HD by investigating its effect on motor and cognitive impairment in the R6/1 mouse model of HD. We found that genetic deletion of STEP delayed the onset of motor dysfunction and prevented the appearance of cognitive deficits in R6/1 mice. This phenotype was accompanied by an increase in pERK1/2 levels, a delay in the decrease of striatal DARPP-32 levels and a reduction in the size of mhtt aggregates, both in the striatum and CA1 hippocampal region. We also found that acute pharmacological inhibition of STEP with TC-2153 improved cognitive function in R6/1 mice. In conclusion, our results show that deletion of STEP has a beneficial effect on motor coordination and cognition in a mouse model of HD suggesting that STEP inhibition could be a good therapeutic strategy in HD patients. |
| Databáze: | OpenAIRE |
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