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.
Highlights
Neurodegenerative diseases are debilitating disorders characterized by the gradual loss of anatomically or physiologically related function or structure of the central nervous system and include various diseases with different pathological patterns and clinical manifestations, such as Alzheimer’s disease (AD), Huntington’s disease (HD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS) [1,2,3]
Many previous studies have demonstrated that expression-level changes in specific neurotrophic factors (NTFs), such as brain-derived neurotrophic factor (BDNF), ciliary neurotrophic factor (CNTF), and glial cell line-derived neurotrophic factor (GDNF), are associated with the pathogenesis of neurodegenerative diseases, such as AD [19,60,61], PD [62,63,64], HD [65,66], and ALS [67,68] (Table 2)
We found that neuronal BDNF produced by AAV serotype 1 (AAV1)-Ras homolog protein enriched in brain (Rheb)(S16H) transduction in hippocampal neurons induced the activation of astrocytes and mediated the production of CNTF through the activation of astrocytic tropomyosin receptor kinase B (TrkB)
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. It has been reported that activation of Rheb can protect neurons against neurotoxic conditions in the adult brain through neurotrophic interactions (such as BDNF, GDNF, and CNTF production) between neurons and astrocytes [39,40,41,42] These findings suggest that Rheb involvement in neurodegenerative diseases and its important role in the production of various NTFs can be considered as one of the potential therapeutic targets for neurodegenerative diseases. Many previous studies have demonstrated that expression-level changes in specific NTFs, such as BDNF, CNTF, and glial cell line-derived neurotrophic factor (GDNF), are associated with the pathogenesis of neurodegenerative diseases, such as AD [19,60,61], PD [62,63,64], HD [65,66], and ALS [67,68] (Table 2)
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