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
Summary
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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