RTP801 is a critical factor in the neurodegeneration process of A53T α‐synuclein in a mouse model of Parkinson's disease under chronic restraint stress

Zhang, Zhao; Chu, Shifeng; Wang, Shasha; Jiang, Yi-Na; Gao, Yan; Yang, Pengfei; Ai, Qidi; Chen, Nai‐Hong

doi:10.1111/bph.14091

Cited by 27 publications

(23 citation statements)

References 55 publications

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“…The fact that silencing RTP801 in WT animals does not affect their performance at this paradigm may suggest that remaining basal levels of RTP801 are sufficient to maintain proper motor-learning plasticity and, therefore, corticostriatal functionality. Highlighting the function of RTP801 in synaptic plasticity, its downregulation in the Substantia Nigra pars compacta has also been shown to restore motor-learning skills in a PD mice model subjected to chronic stress 63 .…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2020

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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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Section: Discussionmentioning

confidence: 99%

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

et al. 2020

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“…GBA1 mutation produces an accumulation of cholesterol, which alters autophagy-lysosome function and impairs autophagy, rendering the neurons more vulnerable and sensitive to apoptosis( Garcia-Sanz et al, 2017 , 2018 ). Elevated RTP801, product of DNA damage inducible transcript 4 , represses autophagy, then increases the accumulation of oligomeric α-synuclein and further aggravates ER stress-induced neuronal apoptosis ( Zhang et al, 2017 ).…”

Section: Mechanisms Of Neuronal Cell Death In Pdmentioning

confidence: 99%

Cellular and Molecular Basis of Neurodegeneration in Parkinson Disease

Zeng

Geng

Jia

et al. 2018

Front. Aging Neurosci.

168

114

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It has been 200 years since Parkinson disease (PD) was described by Dr. Parkinson in 1817. The disease is the second most common neurodegenerative disease characterized by a progressive loss of dopaminergic neurons in the substantia nigra pars compacta. Although the pathogenesis of PD is still unknown, the research findings from scientists are conducive to understand the pathological mechanisms. It is well accepted that both genetic and environmental factors contribute to the onset of PD. In this review, we summarize the mutations of main seven genes (α-synuclein, LRRK2, PINK1, Parkin, DJ-1, VPS35 and GBA1) linked to PD, discuss the potential mechanisms for the loss of dopaminergic neurons (dopamine metabolism, mitochondrial dysfunction, endoplasmic reticulum stress, impaired autophagy, and deregulation of immunity) in PD, and expect the development direction for treatment of PD.

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“…The fact that silencing RTP801 in WT animals does not affect their performance at this paradigm could suggest that remaining basal levels of RTP801 are sufficient to maintain proper motor learning plasticity and, therefore, cortico-striatal functionality. Highlighting the function of RTP801 in synaptic plasticity, its downregulation in the Substantia Nigra pars compacta has also been shown to restore motor learning skills in a PD mice model subjected to chronic stress 68 .…”

Section: Discussionmentioning

confidence: 99%

Synaptic RTP801 Contributes to Motor Learning Dysfunction in Huntington’s Disease

Martín‐Flores

Pérez‐Sisqués

Creus-Muncunill

et al. 2020

Preprint

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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.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 potential role in the human disease. These findings open a new therapeutic framework focused on the RTP801/Akt/mTOR axis.

show abstract

RTP801 is a critical factor in the neurodegeneration process of A53T α‐synuclein in a mouse model of Parkinson's disease under chronic restraint stress

Abstract: RTP801 is a promising target for the treatment of PD, especially for PD-sensitive patients who live under increased social pressure. Down-regulation of RTP801 could inhibit the current tendency to an earlier onset of PD.

Cited by 27 publications

References 55 publications

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

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

Cellular and Molecular Basis of Neurodegeneration in Parkinson Disease

Synaptic RTP801 Contributes to Motor Learning Dysfunction in Huntington’s Disease

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