Abstract

The role of astrocyte elevated gene-1 (AEG-1) in nigral dopaminergic (DA) neurons has not been studied. Here we report that the expression of AEG-1 was significantly lower in DA neurons in the postmortem substantia nigra of patients with Parkinson’s disease (PD) compared to age-matched controls. Similarly, decreased AEG-1 levels were found in the 6-hydroxydopamine (6-OHDA) mouse model of PD. An adeno-associated virus-induced increase in the expression of AEG-1 attenuated the 6-OHDA-triggered apoptotic death of nigral DA neurons. Moreover, the neuroprotection conferred by the AEG-1 upregulation significantly intensified the neurorestorative effects of the constitutively active ras homolog enriched in the brain [Rheb(S16H)]. Collectively, these results demonstrated that the sustained level of AEG-1 as an important anti-apoptotic factor in nigral DA neurons might potentiate the therapeutic effects of treatments, such as Rheb(S16H) administration, on the degeneration of the DA pathway that characterizes PD.

Highlights

  • Astrocyte elevated gene-1 (AEG-1), known as metadherin, was originally identified as a human immunodeficiency virus-1- and tumor necrosis factor-alphainducible gene in human fetal astrocytes, and its upregulation is a well-established important oncogenic event in various types of human cancer[1,2,3,4]

  • Decreased astrocyte elevated gene-1 (AEG-1) expression was not observed in the hippocampus of patients with Alzheimer’s disease (AD) compared to age-matched controls, even though there was a significant loss of neuronal nuclei (NeuN, a marker of neurons) in that region in the patients compared to controls (Fig. 1f, g; #p = 0.001 vs. CON)

  • The inhibition of apoptotic pathways protects DA neurons against neurotoxin treatment[7,27,28,29,30]. These results suggest that the expression and maintenance of endogenous anti-apoptotic factors are beneficial for the survival of nigral DA neurons in the adult brain

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Summary

Introduction

Astrocyte elevated gene-1 (AEG-1), known as metadherin, was originally identified as a human immunodeficiency virus-1- and tumor necrosis factor-alphainducible gene in human fetal astrocytes, and its upregulation is a well-established important oncogenic event in various types of human cancer[1,2,3,4]. The aberrant activation of apoptotic signaling pathways in the adult brain is a well-known neurotoxic event that is associated with neuronal loss, such as that observed in neurodegenerative diseases, including Parkinson’s disease (PD) and Alzheimer’s disease (AD)[6,7,8], and the PI3K/Akt/ mammalian target of rapamycin complex 1 (mTORC1) signaling pathway has been shown to elicit neuroprotective effects on the survival and growth of neurons in the nigrostriatal dopaminergic (DA) system[9,10,11]. PD were associated with significant decreases in the levels of expression of AEG-1 in nigral DA neurons of patients with PD compared to age-matched controls These findings suggested that the relationship between AEG-1 downregulation and the pathogenesis of PD are clinically relevant. We examined whether the neuroprotection conferred by AEG-1 overexpression, which might be a therapeutic intervention, contributed to the neurorestorative effects on the in vivo nigrostriatal DA system of treatment strategies, such as the administration of constitutively active ras homolog enriched in brain (with a S16H mutation) [Rheb(S16H)], which induces axonal regrowth in damaged DA neurons[9,10]

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