Synaptic RTP801 contributes to motor-learning dysfunction in Huntington’s disease.

Synaptic RTP801 contributes to motor-learning dysfunction in Huntington’s disease.

Publication date: Jul 30, 2020

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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Concepts Keywords
Akt D. James Surmeier
Calcium Striatum
Ectopic Neuroplasticity
Huntingtin Synapse
Huntington Synaptic plasticity
Hyperphosphorylation Signal transduction
Motor Learning Neurology
MTOR Neural circuits
Murine Neurophysiology
Mutant Neuroscience
Neurons Brain
Normalized Branches of biology
Postmortem Potential disease
Putamen Motor dysfunction
Rictor
ShRNA
Stress
Striatal
Striatum
Synapses
Synaptic
Synaptic Plasticity
Toxicity
TrkB Receptor
Viral

Semantics

Type Source Name
disease MESH pathology
drug DRUGBANK Ranitidine
drug DRUGBANK Trihexyphenidyl
drug DRUGBANK Profenamine
pathway KEGG Huntington disease
disease MESH Huntington disease
disease MESH growth
disease MESH tumor
pathway KEGG Apoptosis
drug DRUGBANK Phosphate ion
drug DRUGBANK Hydroquinone
disease MESH separated
drug DRUGBANK Potassium Chloride
drug DRUGBANK Sodium bicarbonate
drug DRUGBANK Magnesium sulfate
drug DRUGBANK Glutamic Acid
drug DRUGBANK Sucrose
drug DRUGBANK Oxygen
drug DRUGBANK Isoflurane
drug DRUGBANK Ketamine
drug DRUGBANK Water
drug DRUGBANK Hyaluronic acid
drug DRUGBANK L-Glutamine
drug DRUGBANK Pentaerythritol tetranitrate
drug DRUGBANK Methylergometrine
drug DRUGBANK Nerve Growth Factor
pathway KEGG Insulin resistance
disease MESH insulin resistance
drug DRUGBANK Serine
disease MESH **P
drug DRUGBANK Proline
drug DRUGBANK L-Lysine
drug DRUGBANK Trypsin
drug DRUGBANK L-Leucine
drug DRUGBANK Aminolevulinic acid
drug DRUGBANK Sirolimus
pathway REACTOME Translation
drug DRUGBANK Coenzyme M
pathway KEGG Autophagy
drug DRUGBANK Trestolone
drug DRUGBANK Calcium
disease MESH Death
disease MESH cognitive impairment

Original Article

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