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Synaptic RTP801 contributes to motor-learning dysfunction in Huntington's disease
Núria Martín-Flores1,2, Leticia Pérez-Sisqués3,4, Jordi Creus-Muncunill3,4,5,6
1Department of Biomedicine, Faculty of Medicine, University of Barcelona, 08036, Barcelona, Catalonia, Spain. nuria.martinfl21@gmail.com.
Cell Death & Disease
|August 1, 2020
Summary
Stress-responsive RTP801 (also known as REDD1) protein contributes to mutant huntingtin toxicity and motor deficits in Huntington
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- RTP801/REDD1 is a stress-responsive protein implicated in mutant huntingtin (mhtt) toxicity.
- RTP801 levels are elevated in the putamen of Huntington's disease (HD) patients.
Purpose of the Study:
- To investigate the role of RTP801 in striatal synaptic plasticity and motor impairment in Huntington's disease (HD).
Main Methods:
- Overexpression of ectopic mhtt in cultured rat neurons.
- Assessment of RTP801 protein levels in human postmortem HD brains and HD mouse models.
- Striatal RTP801 knockdown using adeno-associated viral vectors in R6/1 HD mice.
- Evaluation of motor learning in treated mice.
Main Results:
- Ectopic mhtt increased RTP801 in neuronal synapses.
- RTP801 was upregulated in striatal synapses of HD patients and mouse models.
- RTP801 knockdown in R6/1 mice ameliorated motor-learning deficits.
- Silencing RTP801 normalized Akt hyperphosphorylation and increased synaptic GluA1 and TrkB levels, enhancing synaptic plasticity.
Conclusions:
- Mutant huntingtin-induced RTP801 mediates motor dysfunction in HD models.
- RTP801 plays a role in the pathophysiology of Huntington's disease.
- Targeting the RTP801/Akt/mTOR pathway offers a potential therapeutic strategy for HD.
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