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Title: Synaptic RTP801 contributes to motor-learning dysfunction in Huntington's disease
Author: Martín Flores, Núria
Pérez Sisqués, Leticia
Creus Muncunill, Jordi
Masana Nadal, Mercè
Ginés Padrós, Silvia
Alberch i Vié, Jordi
Pérez Navarro, Esther
Malagelada Grau, Cristina
Keywords: Corea de Huntington
Huntington's chorea
Issue Date: 30-Jul-2020
Publisher: Nature Publishing Group
Abstract: RTP801/REDD1 is a stress-responsive protein that mediates mutant huntingtin (mhtt) toxicity in cellular models and is up regulated in Huntington's disease (HD) patients' putamen. Here, we investigated whether RTP801 is involved in motor impairment in HD by affecting striatal synaptic plasticity. To explore this hypothesis, ectopic mhtt was over expressed in cultured rat primary neurons. Moreover, the protein levels of RTP801 were assessed in homogenates and crude synaptic fractions from human postmortem HD brains and mouse models of HD. Finally, striatal RTP801 expression was knocked down with adeno-associated viral particles containing a shRNA in the R6/1 mouse model of HD and motor learning was then tested. Ectopic mhtt elevated RTP801 in synapses of cultured neurons. RTP801 was also up regulated in striatal synapses from HD patients and mouse models. Knocking down RTP801 in the R6/1 mouse striatum prevented motor-learning impairment. RTP801 silencing normalized the Ser473 Akt hyperphosphorylation by downregulating Rictor and it induced synaptic elevation of calcium permeable GluA1 subunit and TrkB receptor levels, suggesting an enhancement in synaptic plasticity. These results indicate that mhtt-induced RTP801 mediates motor dysfunction in a HD murine model, revealing a potential role in the human disease. These findings open a new therapeutic framework focused on the RTP801/Akt/mTOR axis.
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It is part of: Cell Death and Disease, 2020, vol. 11, num. 7, p. 569
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ISSN: 2041-4889
Appears in Collections:Articles publicats en revistes (Biomedicina)
Articles publicats en revistes (IDIBAPS: Institut d'investigacions Biomèdiques August Pi i Sunyer)
Articles publicats en revistes (Institut de Neurociències (UBNeuro))

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