Anna Bellizzi

Circular RNAs (circRNAs) represent a class of highly stable, covalently closed RNA molecules increasingly recognized as important regulators of brain aging and neurodegenerative disease. Growing evidence also implies circRNAs in viral infection, suggesting a potential intersection between viral neuropathogenesis and neurodegeneration. However, no studies have yet directly integrated circRNAs, neurotropic viral infections, and neurodegenerative disorders within a single mechanistic framework. To date, specific circRNAs have been linked to the progression of Alzheimer’s disease and Parkinson’s disease, where they regulate central pathological processes including amyloid-β clearance, neuroinflammation, synaptic plasticity, neuronal apoptosis, and oxidative stress. Moreover, it has been established that both host cells and viruses produce circRNAs during infection. Virus-derived circRNAs can enhance viral replication, promote immune evasion, and support latency. In contrast, host circRNAs contribute to antiviral defense by acting as microRNA sponges, interacting with viral proteins, or encoding peptides with antiviral activity, mechanisms particularly explored in viral oncogenesis. In this review, we will evaluate the most updated research evidence on the role of circRNAs in major neurodegenerative diseases and neurotropic viral infections. Considering the growing concern regarding the long-term neurological consequences of viral infections, including chronic neuroinflammation, viral reactivation, and post-viral syndromes, dysregulated circRNAs may represent a mechanistic link between viral infection and associated neurodegenerative processes. Finally, we will discuss future directions for identifying circRNAs-based biomarkers and developing circRNAs-targeted therapeutic strategies for age-related and virus-associated neurological disorders.

Alzheimer's disease (AD) is characterized by progressive cognitive decline, memory loss, and behavioral changes. AD is pathologically marked by the accumulation of extracellular amyloid-β (Aβ) oligomers, amyloidogenic plaques, and intracellular neurofibrillary tangles. Amyloid-β protein precursor (AβPP) plays a central role in AD pathology, as it is cleaved by β-secretase and γ-secretase enzymes to generate Aβ peptides and oligomers which aggregate to form neurotoxic fibrils and plaques in the brain. Increased AβPP expression has been correlated to Aβ suggesting a larger role for AβPP function potentially through AβPP isoforms. Alternative splicing (AS) of APP pre-mRNA has emerged as a key regulatory mechanism influencing AβPP function through the generation of distinct isoforms. Similarly, the microtubule-associated protein tau (MAPT) is also subject to alternative splicing, producing isoforms that can contribute to hyperphosphorylation and neurodegeneration. In this review, we explore the role of APP alternative splicing and the regulation of its isoform expression in AD and other neurodegenerative disorders, with a focus on its potential impact on Aβ peptide production. We also discuss recent advances in therapies targeting dysregulated splicing in neurodegenerative diseases and their potential relevance to AD. Finally, we highlight the use of three-dimensional culture models as a platform to study AS regulation in AD and other neurodegeneration-related disorders.

Polyomavirus JC (JCPyV) causes the demyelinating disease progressive multifocal leukoencephalopathy (PML). JCPyV infection is very common in childhood and, under conditions of severe immunosuppression, JCPyV may reactivate to cause PML. JC viral proteins expression is regulated by the JCPyV non-coding control region (NCCR), which contains binding sites for cellular transcriptional factors which regulate JCPyV transcription. Our earlier studies suggest that JCPyV reactivation occurs within glial cells due to cytokines such as TNF-α which stimulate viral gene expression. In this study, we examined interferon-α (IFNα) or β (IFNβ) which have a negative effect on JCPyV transcriptional regulation. We also showed that these interferons induce the endogenous liver inhibitory protein (LIP), an isoform of CAAT/enhancer binding protein beta (C/EBPβ). Treatment of glial cell line with interferons increases the endogenous level of C/EBPβ-LIP. Furthermore, we showed that the negative regulatory role of the interferons in JCPyV early and late transcription and viral replication is more pronounced in the presence of C/EBPβ-LIP. Knockdown of C/EBPβ-LIP by shRNA reverse the inhibitory effect on JCPyV viral replication. Therefore, IFNα and IFNβ negatively regulate JCPyV through induction of C/EBPβ-LIP, which together with other cellular transcriptional factors may control the balance between JCPyV latency and activation.

Cancer is the second leading cause of mortality worldwide. The study of DNA tumor-inducing viruses and their oncoproteins as a causative agent in cancer initiation and tumor progression has greatly enhanced our understanding of cancer cell biology. The initiation of oncogenesis is a complex process. Specific gene mutations cause functional changes in the cell that ultimately result in the inability to regulate cell differentiation and proliferation effectively. The human neurotropic Polyomavirus JC (JCV) belongs to the family Polyomaviridae and it is the causative agent of progressive multifocal leukoencephalopathy (PML), which is a fatal neurodegenerative disease in an immunosuppressed state. Sero-epidemiological studies have indicated JCV infection is prevalent in the population (85%) and that initial infection usually occurs during childhood. The JC virus has small circular, double-stranded DNA that includes coding sequences for viral early and late proteins. Persistence of the virus in the brain and other tissues, as well as its potential to transform cells, has made it a subject of study for its role in brain tumor development. Earlier observation of malignant astrocytes and oligodendrocytes in PML, as well as glioblastoma formation in non-human primates inoculated with JCV, led to the hypothesis that JCV plays a role in central nervous system (CNS) tumorigenesis. Some studies have reported the presence of both JC viral DNA and its proteins in several primary brain tumor specimens. The discovery of new Polyomaviruses such as the Merkel cell Polyomavirus, which is associated with Merkel cell carcinomas in humans, ignited our interest in the role of the JC virus in CNS tumors. The current evidence known about JCV and its effects, which are sufficient to produce tumors in animal models, suggest it can be a causative factor in central nervous system tumorigenesis. However, there is no clear association between JCV presence in CNS and its ability to initiate CNS cancer and tumor formation in humans. In this review, we will discuss the correlation between JCV and tumorigenesis of CNS in animal models, and we will give an overview of the current evidence for the JC virus’s role in brain tumor formation.