title: Understanding the role of miRNAs in neuroinflammation
Creators: name: James, Brandon C
Publisher: name: Griffith University
Year: 2022
Subjects: subject: α-synuclein
subject: neuroinflammation
subject: alcoholism
subject: miRNA-7 (miR-7)
subject: miRNA-153 (miR- 153)
subject: miRNA-203 (miR-203)
subject: sex
subject: liver cirrhosis

description: Chronic alcohol abuse is a key component of alcohol use disorder and leads to adverse changes in localised regions of the human brain (Zahr &amp; Pfefferbaum, 2017). The prefrontal cortex is particularly susceptible to damage following chronic alcohol abuse (Abernathy et al., 2010). Differential gene expression in the prefrontal cortex has been identified between alcoholics and controls, and includes genes related to immune/stress response (Liu et al., 2006). A chronic immune response in the central nervous system, termed neuroinflammation, has been implicated in the progression of alcohol-induced brain damage (Crews &amp; Vetreno, 2014). Liver cirrhosis, a common co-morbid condition of chronic alcohol abuse, worsens alcohol-induced brain damage (Zahr &amp; Pfefferbaum, 2017). Differential gene expression in the prefrontal cortex has been identified between alcoholics without liver cirrhosis (uncomplicated alcoholics) and alcoholics with liver cirrhosis (cirrhotic alcoholics) (Liu et al., 2007). Furthermore, females have more advanced neurodegeneration following chronic alcohol abuse (Ceylan-Isik et al., 2010). MicroRNAs (miRNAs) are a subclass of non-coding RNAs that regulate messenger RNA (mRNA) expression by binding to complementary seed sequences (O'Brien et al., 2018). Approximately 35 up-regulated miRNAs have been identified in the prefrontal cortex of human alcoholics (Lewohl et al., 2011). Dysregulation of miRNA expression following chronic alcohol abuse may result in the gene expression changes seen in alcoholics (Lewohl et al., 2011; Liu et al., 2007; Liu et al., 2006). As part of this thesis, original research articles related to α-synuclein, neuroinflammation, and alcoholism were reviewed and evaluated. The SNCA gene, which encodes α-synuclein, has been identified as a top candidate gene for alcoholism (Levey et al., 2014). No articles included information relating to all three of these topics, suggesting that the link between these three topics is yet to be identified. Toll-like receptor (TLR) 4, an innate immune receptor, was commonly studied in the field of alcoholism. Studies in humans used a variety of diagnostic criteria for the diagnosis of alcoholism. Studies in animals used a variety of alcohol exposure paradigms. Thus, a lack of consistency in diagnostic criteria for humans and animal models may complicate the interpretation of data derived from different studies. This thesis investigated differences in miRNA-7 (miR-7), miRNA-153 (miR-153), and miRNA-203 (miR-203) expression in the dorsolateral prefrontal cortex (prefrontal cortex) between controls, uncomplicated alcoholics, and cirrhotic alcoholics. Males and females were analysed separately to identify sex-specific changes in miRNA expression. Expression of miR-7, miR-153, and miR-203 was significantly higher in male uncomplicated alcoholics and cirrhotic alcoholics compared to controls. There were no differences in miR-7, miR-153, or miR-203 expression between controls, uncomplicated alcoholics, or cirrhotic alcoholics in females. MiR-153 has previously been validated to regulate the expression of wild-type α- synuclein (SNCA-140) (Doxakis, 2010). MiR-203 is predicted to target the α-synuclein splice variant SNCA-115 (McGeary et al., 2019). As part of my study, neuron-like cell cultures were treated with mimics or inhibitors of miR-153 or miR-203 to investigate their effect on SNCA-140, SNCA-112, and SNCA-115 expression. A 2.3-fold increase in SNCA-115 expression was identified 48 h after treatment with miR-203 inhibitor. The findings of this thesis highlight the effect of sex and liver cirrhosis in miRNA expression changes following chronic alcohol abuse. Regulation of α-synuclein splice variant expression by miRNAs may play a role in mediating the reward pathway (Butler et al., 2017) or alcohol-induced brain damage (Bennett, 2005). Understanding the mechanisms that underlie miRNA-mediated α-synuclein splice variant expression may enhance understanding of neuroinflammation and neuron function that results from chronic alcohol abuse.