Apr 9, 2020

SYNAPTIC RTP801 CONTRIBUTES TO MOTOR LEARNING DYSFUNCTION IN HUNTINGTON DISEASE

BioRxiv : the Preprint Server for Biology
Núria Martín-FloresCristina Malagelada

Abstract

RTP801/REDD1 is a stress responsive protein that mediates mutant huntingtin (mhtt) toxicity in cellular models and is up regulated in Huntington disease (HD) patients putamen. Here, we investigated whether RTP801 is involved in motor impairment in HD by affecting striatal synaptic plasticity. Ectopic mhtt was over expressed in cultured rat primary neurons. The protein levels of RTP801 were assessed in homogenates and crude synaptic fractions from human postmortem HD brains and mouse models of HD. 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 pot...Continue Reading

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Mentioned in this Paper

Biological Markers
Transformation, Genetic
DONS
Pterois radiata
Agrobacterium tumefaciens
Coculture Techniques
Basta
Inocybe radiata
Agrobacterium
Chimera Organism

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