Roles of Rheb(S16H) in substantia nigra pars compacta dopaminergic neurons in vivo

Jeon, Min‐Tae; Kim, Sang Ryong

doi:10.3892/br.2014.397

Cited by 7 publications

(7 citation statements)

References 33 publications

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“…In particular, Rheb(S16H) upregulation by adeno-associated virus serotype 1 (AAV1) administration in nigral dopaminergic neurons significantly increased the activation of mTORC1, resulting in greater neuroprotective effects compared with Rheb(N153T) upregulation in the animal model of PD [24]. In addition, our studies demonstrated that the upregulation of neuronal Rheb(S16H) could protect neurons against neurodegeneration and promote axonal regrowth in the nigrostriatal dopamine system and hippocampus of the adult brain [11,24,25,30,69,134]. The activation of mTORC1 induced by Rheb(S16H) transduction of hippocampal neurons was found to result in BDNF production, which protected against thrombin-induced neurotoxicity in the rat hippocampus [5].…”

Section: Mutation Of Rheb Leading To Constitutive Activationmentioning

confidence: 78%

Upregulation of Neuronal Rheb(S16H) for Hippocampal Protection in the Adult Brain

Moon

Shin

Kim

2020

IJMS

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Ras homolog protein enriched in brain (Rheb) is a key activator of mammalian target of rapamycin complex 1 (mTORC1). The activation of mTORC1 by Rheb is associated with various processes such as protein synthesis, neuronal growth, differentiation, axonal regeneration, energy homeostasis, autophagy, and amino acid uptake. In addition, Rheb–mTORC1 signaling plays a crucial role in preventing the neurodegeneration of hippocampal neurons in the adult brain. Increasing evidence suggests that the constitutive activation of Rheb has beneficial effects against neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). Our recent studies revealed that adeno-associated virus serotype 1 (AAV1) transduction with Rheb(S16H), a constitutively active form of Rheb, exhibits neuroprotective properties through the induction of various neurotrophic factors, promoting neurotrophic interactions between neurons and astrocytes in the hippocampus of the adult brain. This review provides compelling evidence for the therapeutic potential of AAV1–Rheb(S16H) transduction in the hippocampus of the adult brain by exploring its neuroprotective effects and mechanisms.

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Section: Mutation Of Rheb Leading To Constitutive Activationmentioning

confidence: 78%

Upregulation of Neuronal Rheb(S16H) for Hippocampal Protection in the Adult Brain

Moon

Shin

Kim

2020

IJMS

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“…NSC self-renewal and differentiation are vital processes at various stages of brain development. Overactive mTORC1 encourages NSC differentiation at the expense of self-renewal in neonatal NSCs, while reduced mTORC1 activity prevents differentiation, resulting in fewer neurons [103]. Additionally, due to its involvement in Reelin-Dab signaling, constant activation of Rheb1 in NPCs influences neuroblast migration [104].…”

Section: Rheb1 In Neural Stem Cell Differentiationmentioning

confidence: 99%

Unraveling the Role of Ras Homolog Enriched in Brain (Rheb1 and Rheb2): Bridging Neuronal Dynamics and Cancer Pathogenesis through Mechanistic Target of Rapamycin Signaling

Rahman,

Nguyen,

Lee

et al. 2024

IJMS

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Ras homolog enriched in brain (Rheb1 and Rheb2), small GTPases, play a crucial role in regulating neuronal activity and have gained attention for their implications in cancer development, particularly in breast cancer. This study delves into the intricate connection between the multifaceted functions of Rheb1 in neurons and cancer, with a specific focus on the mTOR pathway. It aims to elucidate Rheb1’s involvement in pivotal cellular processes such as proliferation, apoptosis resistance, migration, invasion, metastasis, and inflammatory responses while acknowledging that Rheb2 has not been extensively studied. Despite the recognized associations, a comprehensive understanding of the intricate interplay between Rheb1 and Rheb2 and their roles in both nerve and cancer remains elusive. This review consolidates current knowledge regarding the impact of Rheb1 on cancer hallmarks and explores the potential of Rheb1 as a therapeutic target in cancer treatment. It emphasizes the necessity for a deeper comprehension of the molecular mechanisms underlying Rheb1-mediated oncogenic processes, underscoring the existing gaps in our understanding. Additionally, the review highlights the exploration of Rheb1 inhibitors as a promising avenue for cancer therapy. By shedding light on the complicated roles between Rheb1/Rheb2 and cancer, this study provides valuable insights to the scientific community. These insights are instrumental in guiding the identification of novel targets and advancing the development of effective therapeutic strategies for treating cancer.

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“…Our previous studies also demonstrated that the substitution of serine by histidine at position 16 of Rheb [Rheb(S16H)] significantly induced the expression of NTFs, such as GDNF, CNTF, and BDNF in the adult brain [ 39 , 42 , 69 , 73 , 74 , 179 , 180 ]. Our studies further showed that the upregulation of neuronal Rheb(S16H) protects neurons from neuronal degeneration and promotes axonal regrowth in the hippocampus and the nigrostriatal dopamine system of the adult brain [ 41 , 73 , 74 , 149 , 150 , 180 ]. Our laboratory research further demonstrated that the activation of mTORC1 induced by Rheb(S16H) transduction in hippocampal neurons led to BDNF production, which protected the rat hippocampus against thrombin-induced neurotoxicity [ 40 ].…”

Section: Therapeutic Potential Of Rheb(s16h) Transduction Via Aav1mentioning

confidence: 99%

Therapeutic Potential of AAV1-Rheb(S16H) Transduction against Neurodegenerative Diseases

Nam

Moon

Kim

2021

IJMS

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Neurotrophic factors (NTFs) are essential for cell growth, survival, synaptic plasticity, and maintenance of specific neuronal population in the central nervous system. Multiple studies have demonstrated that alterations in the levels and activities of NTFs are related to the pathology and symptoms of neurodegenerative disorders, such as Parkinson’s disease (PD), Alzheimer’s disease (AD), and Huntington’s disease. Hence, the key molecule that can regulate the expression of NTFs is an important target for gene therapy coupling adeno-associated virus vector (AAV) gene. We have previously reported that the Ras homolog protein enriched in brain (Rheb)–mammalian target of rapamycin complex 1 (mTORC1) axis plays a vital role in preventing neuronal death in the brain of AD and PD patients. AAV transduction using a constitutively active form of Rheb exerts a neuroprotective effect through the upregulation of NTFs, thereby promoting the neurotrophic interaction between astrocytes and neurons in AD conditions. These findings suggest the role of Rheb as an important regulator of the regulatory system of NTFs to treat neurodegenerative diseases. In this review, we present an overview of the role of Rheb in neurodegenerative diseases and summarize the therapeutic potential of AAV serotype 1 (AAV1)-Rheb(S16H) transduction in the treatment of neurodegenerative disorders, focusing on diseases, such as AD and PD.

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Roles of Rheb(S16H) in substantia nigra pars compacta dopaminergic neurons in vivo

Cited by 7 publications

References 33 publications

Upregulation of Neuronal Rheb(S16H) for Hippocampal Protection in the Adult Brain

Upregulation of Neuronal Rheb(S16H) for Hippocampal Protection in the Adult Brain

Unraveling the Role of Ras Homolog Enriched in Brain (Rheb1 and Rheb2): Bridging Neuronal Dynamics and Cancer Pathogenesis through Mechanistic Target of Rapamycin Signaling

Therapeutic Potential of AAV1-Rheb(S16H) Transduction against Neurodegenerative Diseases

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