The Path to microRNA Therapeutics in Psychiatric and Neurodegenerative Disorders

The microRNA (miRNA) class of non-coding RNAs exhibit a diverse range of regulatory roles in neuronal functions that are conserved from lower vertebrates to primates. Disruption of miRNA expression has compellingly been linked to pathogenesis in neuropsychiatric and neurodegenerative disorders, such as schizophrenia, Alzheimer’s disease, and autism. The list of transcript targets governed by a single miRNA provide a molecular paradigm applicable for therapeutic intervention. Indeed, reports have shown that specific manipulation of a miRNA in cell or animal models can significantly alter phenotypes linked with neurological disease. Here, we review how a diverse range of biological systems, including Drosophila, rodents, and primates such as monkeys and humans, can be integrated into the translation of miRNAs as novel clinical targets

microRNA-128a dysregulation in transgenic Huntington’s disease monkeys

BACKGROUND: Huntington’s Disease (HD) is a progressive neurodegenerative disorder with a single causal mutation in the Huntingtin (HTT) gene. MicroRNAs (miRNAs) have recently been implicated as epigenetic regulators of neurological disorders, however, their role in HD pathogenesis is not well defined. Here we study transgenic HD monkeys (HD monkeys) to examine miRNA dysregulation in a primate model of the disease. RESULTS: In this report, 11 miRNAs were found to be significantly associated (P value < 0.05) with HD in the frontal cortex of the HD monkeys. We further focused on one of those candidates, miR-128a, due to the corresponding disruption in humans and mice with HD as well as its intriguing lists of gene targets. miR-128a was downregulated in our HD monkey model by the time of birth. We then confirmed that miR-128a was also downregulated in the brains of pre-symptomatic and post-symptomatic HD patients. Additionally, our studies confirmed a panel of canonical HD signaling genes regulated by miR-128a, including HTT and Huntingtin Interaction Protein 1 (HIP1). CONCLUSION: Our studies found that miR-128a may play a critical role in HD and could be a viable candidate as a therapeutic or biomarker of the disease

A two years longitudinal study of a transgenic Huntington disease monkey

BACKGROUND: A two-year longitudinal study composed of morphometric MRI measures and cognitive behavioral evaluation was performed on a transgenic Huntington’s disease (HD) monkey. rHD1, a transgenic HD monkey expressing exon 1 of the human gene encoding huntingtin (HTT) with 29 CAG repeats regulated by a human polyubiquitin C promoter was used together with four age-matched wild-type control monkeys. This is the first study on a primate model of human HD based on longitudinal clinical measurements. RESULTS: Changes in striatal and hippocampal volumes in rHD1 were observed with progressive impairment in motor functions and cognitive decline, including deficits in learning stimulus-reward associations, recognition memory and spatial memory. The results demonstrate a progressive cognitive decline and morphometric changes in the striatum and hippocampus in a transgenic HD monkey. CONCLUSIONS: This is the first study on a primate model of human HD based on longitudinal clinical measurements. While this study is based a single HD monkey, an ongoing longitudinal study with additional HD monkeys will be important for the confirmation of our findings. A nonhuman primate model of HD could complement other animal models of HD to better understand the pathogenesis of HD and future development of diagnostics and therapeutics through longitudinal assessment

Altered microRNA expression in frontotemporal lobar degeneration with TDP-43 pathology caused by progranulin mutations

<p>Abstract</p> <p>Background</p> <p>Frontotemporal lobar degeneration (FTLD) is a progressive neurodegenerative disorder that can be triggered through genetic or sporadic mechanisms. MicroRNAs (miRNAs) have become a major therapeutic focus as their pervasive expression and powerful regulatory roles in disease pathogenesis become increasingly apparent. Here we examine the role of miRNAs in FTLD patients with TAR DNA-binding protein 43 pathology (FTLD-TDP) caused by genetic mutations in the progranulin (<it>PGRN</it>) gene.</p> <p>Results</p> <p>Using miRNA array profiling, we identified the 20 miRNAs that showed greatest evidence (unadjusted P < 0.05) of dysregulation in frontal cortex of eight FTLD-TDP patients carrying <it>PGRN </it>mutations when compared to 32 FTLD-TDP patients with no apparent genetic abnormalities. Quantitative real-time PCR (qRT-PCR) analyses provided technical validation of the differential expression for 9 of the 20 miRNAs in frontal cortex. Additional qRT-PCR analyses showed that 5 out of 9 miRNAs (miR-922, miR-516a-3p, miR-571, miR-548b-5p, and miR-548c-5p) were also significantly dysregulated (unadjusted P < 0.05) in cerebellar tissue samples of <it>PGRN </it>mutation carriers, consistent with a systemic reduction in PGRN levels. We developed a list of gene targets for the 5 candidate miRNAs and found 18 genes dysregulated in a reported FTLD mRNA study to exhibit anti-correlated miRNA-mRNA patterns in affected cortex and cerebellar tissue. Among the targets is brain-specific angiogenesis inhibitor 3, which was recently identified as an important player in synapse biology.</p> <p>Conclusions</p> <p>Our study suggests that miRNAs may contribute to the pathogenesis of FTLD-TDP caused by <it>PGRN </it>mutations and provides new insight into potential future therapeutic options.</p

Advances in non-coding RNA profiling for neurological diseases

Over the past decade, the classifications and volume of non-coding RNA (ncRNA) transcripts have grown profoundly, spurred by transcriptomic sequencing efforts (Bartel, 2009; Guttman et al., 2009; Djebali et al., 2012). This has identified an array of human disorders associated with some degree of ncRNA dysregulation (Taft et al., 2010), prompting an expanding need to characterize ncRNA expression in targeted tissues. Brain disorders, including neurodegenerative and psychiatric disease, have increasingly been the subject of ncRNA profiling studies (Kocerha et al., 2009a,b; Beveridge et al., 2010; Im and Kenny, 2012). The technology to probe for ncRNA expression, however, varies, depending on the class of transcripts to be examined. Arguably, to date, the resources to assess microRNA (miRNA) expression are the most comprehensive, spanning from classic hybridization arrays to real-time PCR arrays. However, with the discovery of long ncRNAs (lncRNAs) in the brain, such as natural antisense transcripts (NATs) and large intergenic non-coding (Linc) RNAs (Guttman et al., 2009; Modarresi et al., 2012), the access to new technology for examination of those transcripts is also expanding

microRNAs in CNS disorders

In recent years, there has been a shift in the conventional paradigms for transcriptional and translational regulation as extensive sequencing efforts have yielded new insights into the landscape of the human genome and transcriptome. Hundreds of non-coding regulatory RNA molecules called microRNAs (miRNAs) have been identified in the mammalian central nervous system (CNS) and are reported to mediate pivotal roles in many aspects of neuronal functions. Disruption of miRNA-based post-transcriptional regulation has been implicated in a range of CNS disorders as one miRNA is predicted to impact the expression of numerous downstream mRNA targets. The intricate molecular networks mediated by an miRNA form a robust mechanism for rapid and potent responses to cellular events throughout the development of the human brain. Recent studies have identified a molecular and ultimately pathogenic role for a subset of miRNAs in Alzheimer's disease and schizophrenia, including the characterization of their downstream CNS mRNA targets, such as beta-secretase (BACE1) and calmodulin-dependent protein kinase II (CaMKII). Here, we present an overview of the current progress in miRNA research related to CNS disorders and also highlight the utility of LNA (locked nucleic acid)-modified oligonucleotides in the detection and modulation of miRNA activity

MicroRNA Networks in Cognition and Dementia

The change from viewing noncoding RNA as &ldquo;junk&rdquo; in the genome to seeing it as a critical epigenetic regulator in almost every human condition or disease has forced a paradigm shift in biomedical and clinical research. Small and long noncoding RNA transcripts are now routinely evaluated as putative diagnostic or therapeutic agents. A prominent role for noncoding microRNAs in the central nervous system has uncovered promising new clinical candidates for dementia-related disorders, treatments for which currently remain elusive even as the percentage of diagnosed patients increases significantly. Cognitive decline is a core neurodegenerative process in Alzheimer&rsquo;s Disease, Frontotemporal Dementia, Lewy body dementia, vascular dementia, Huntington&rsquo;s Disease, Creutzfeldt&ndash;Jakob disease, and a significant portion of Parkinson&rsquo;s Disease patients. This review will discuss the microRNA-associated networks which influence these pathologies, including inflammatory and viral-mediated pathways (such as the novel SARS-CoV-2 virus implicated in COVID-19), and their current status in clinical trials

Noncoding RNA regulation of dopamine signaling in diseases of the central nervous system

Dopaminergic neurotransmission mediates a majority of the vital central nervous system functions. Disruption of these synaptic events provokes a multitude of neurological pathologies, including Parkinson’s, schizophrenia, depression and addiction. Growing evidence supports a key role for noncoding RNA (ncRNA) regulation in the synapse. This review will discuss the role of both short and long ncRNAs in dopamine signaling, including bioinformatic examination of the pathways they target. Specifically, we focus on the contribution of ncRNAs to dopaminergic dysfunction in neurodegenerative as well as psychiatric disease