Neurodegenerative diseases with distinct genetic etiologies and pathological phenotypes appear to share common mechanisms of neuronal cellular dysfunction, including excitotoxicity, calcium dysregulation, oxidative damage, ER stress and mitochondrial dysfunction. Glial cells, including microglia and astrocytes, play an increasingly recognized role in both the promotion and prevention of neurodegeneration. Sigma receptors, particularly the sigma-1 receptor subtype, which are expressed in both neurons and glia of multiple regions within the central nervous system, are a unique class of intracellular proteins that can modulate many biological mechanisms associated with neurodegeneration. These receptors therefore represent compelling putative targets for pharmacologically treating neurodegenerative disorders. In this review, we provide an overview of the biological mechanisms frequently associated with neurodegeneration, and discuss how sigma-1 receptors may alter these mechanisms to preserve or restore neuronal function. In addition, we speculate on their therapeutic potential in the treatment of various neurodegenerative disorders.

Polygenetic risk factors and reduced expression of many genes in late-onset Alzheimer’s disease (AD) impedes identification of a target(s) for disease-modifying therapies. We identified a single microRNA, miR-34a that is over expressed in specific brain regions of AD patients as well as in the 3xTg-AD mouse model. Specifically, increased miR-34a expression in the temporal cortex region compared to age matched healthy control correlates with severity of AD pathology. miR-34a over expression in patient’s tissue and forced expression in primary neuronal culture correlates with concurrent repression of its target genes involved in synaptic plasticity, oxidative phosphorylation and glycolysis. The repression of oxidative phosphorylation and glycolysis related proteins correlates with reduced ATP production and glycolytic capacity, respectively. We also found that miR-34a overexpressed neurons secrete miR-34a containing exosomes that are taken up by neighboring neurons. Furthermore, miR-34a targets dozens of genes whose expressions are known to be correlated with synchronous activity in resting state functional networks. Our analysis of human genomic sequences from the tentative promoter of miR-34a gene shows the presence of NFκB, STAT1, c-Fos, CREB and p53 response elements. Together, our results raise the possibilities that pathophysiology-induced activation of specific transcription factor may lead to increased expression of miR-34a gene and miR-34a mediated concurrent repression of its target genes in neural networks may result in dysfunction of synaptic plasticity, energy metabolism, and resting state network activity. Thus, our results provide insights into polygenetic AD mechanisms and disclose miR-34a as a potential therapeutic target for AD.

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