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

Abstract

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.

Keywords: Alzheimer’s disease; Parkinson’s disease; Rheb(S16H); neurodegenerative disease; neurotrophic factor.

Figure 1

Rheb-mTORC1 signaling pathway in neurodegeneration. Binding of growth factors, such as insulin or insulin-like growth factor (IGF), to receptors stimulates PI3K signaling. The activity of PI3K-AKT mediates the activation of Rheb-mTORC1 by disinhibiting the Rheb-inhibiting TCS complex. Fully activated Rheb-mTORC1 phosphorylates S6K-1 or 4E-BP1 activate the protein of the translation machinery. In neurodegenerative diseases, Rheb-mTORC1 has negative effects, such as inhibition of autophagy, but promotes cell growth, regeneration, and neuroprotection by regulating the expression of neurotrophic factors, exon regeneration, and anti-apoptosis. In addition, Rheb inhibits Aβ formation through the induction of lysosomal and proteasomal degradation by binding to beta-secretase 1 (BACE) in Alzheimer’s disease (AD) conditions.

Figure 2

Schematic representation of the mechanisms of a neuroprotective system following AAV-hRheb(S16H) transduction in neurodegenerative diseases. In neurodegenerative diseases, various neurotoxicities, including Aβ deposition, α-synuclein aggregation, and inflammatory responses, induce axon loss and demyelination of specific neurons as well as reduction of neurotrophic factors (NTFs), leading to decreased memory/cognition and movement decline. hRheb(S16H) transduction of hippocampal or SNpc neurons using adeno-associated virus serotype 1 (AAV1) can induce the activation of mTORC1, which in turn stimulates the production of NTFs, such as brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), and ciliary neurotrophic factor (CNTF) in the neurons. Increased BDNF and GDNF expressions contribute to neuroprotection through the activation of TrkB/GFRα-1 receptor, in the hippocampus and SNpc of brain, respectively. Moreover, CNTF production by hRheb(S16H) expression in SNpc neurons mediates neuroprotective effects through the CNTFRα receptor. In addition, BDNF/GDNF expression induced in hRheb(S16H)-expressing neurons result in functional interactions between neurons and astrocytes in the hippocampus, leading to the production of astrocytic CNTF and GDNF for hippocampal protection.