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Pharmacogenetic modulation of STEP improves motor and cognitive function in a mouse model of Huntington's disease
Marta García-Forn1, Sara Martínez-Torres2, Gerardo García-Díaz Barriga1
1Departament de Biomedicina, Facultat de Medicina i Ciències de la Salut, Institut de Neurociències, Universitat de Barcelona, Barcelona, Catalonia, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Catalonia, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Spain.
Insights
Huntington's disease (HD) research shows that inhibiting STriatal-Enriched protein tyrosine Phosphatase (STEP) can improve motor and cognitive functions in mice. STEP inactivation offers a potential therapeutic strategy for HD patients.
Area of Science:
- Neuroscience
- Genetics
- Pharmacology
Background:
- Huntington's disease (HD) is a hereditary neurodegenerative disorder.
- CAG repeat expansion in the huntingtin (htt) gene causes aberrant huntingtin protein (mhtt).
- STEP, a neural-specific tyrosine phosphatase, is decreased in HD patients and R6/1 mice.
Purpose of the Study:
- Investigate the role of STEP inactivation in HD pathophysiology.
- Analyze the effect of STEP on motor and cognitive impairment in the R6/1 mouse model.
Main Methods:
- Genetic deletion of STEP in R6/1 mice.
- Pharmacological inhibition of STEP using TC-2153.
- Assessment of motor and cognitive functions.
- Analysis of pERK1/2 and DARPP-32 levels.
- Evaluation of mhtt aggregate size.
Main Results:
- Genetic deletion of STEP delayed motor dysfunction and prevented cognitive deficits in R6/1 mice.
- STEP deletion increased pERK1/2 levels and delayed DARPP-32 decrease.
- Reduced mhtt aggregate size in the striatum and hippocampus was observed.
- Pharmacological STEP inhibition improved cognitive function in R6/1 mice.
Conclusions:
- STEP inactivation has a beneficial effect on motor coordination and cognition in HD mouse models.
- STEP inhibition represents a potential therapeutic strategy for Huntington's disease.
Abstract:
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.