Unravelling the contribution of small non-coding RNAs to Huntington’s disease pathogenesis
[eng] BACKGROUND AND OBJECTIVES: Huntington's disease (HD) is an autosomal dominant neurodegenerative disease caused by an abnormal expansion in the number of CAG triplets located at exon 1 of the huntingtin gene (HTT), resulting in an expanded portion of glutamines (polyQ) in a region near the...
| Autor: | |
|---|---|
| Tipo de recurso: | tesis doctoral |
| Estado: | Versión publicada |
| Fecha de publicación: | 2023 |
| País: | España |
| Institución: | Universidad de Barcelona |
| Repositorio: | Dipòsit Digital de la UB |
| OAI Identifier: | oai:diposit.ub.edu:2445/223319 |
| Acceso en línea: | https://hdl.handle.net/2445/223319 http://hdl.handle.net/10803/695258 |
| Access Level: | acceso abierto |
| Palabra clave: | Neurociències Corea de Huntington Neurotoxicologia RNA Neurosciences Huntington's chorea Neurotoxicology |
| Sumario: | [eng] BACKGROUND AND OBJECTIVES: Huntington's disease (HD) is an autosomal dominant neurodegenerative disease caused by an abnormal expansion in the number of CAG triplets located at exon 1 of the huntingtin gene (HTT), resulting in an expanded portion of glutamines (polyQ) in a region near the amino terminal end of the HTT protein (The Huntington's Disease Collaborative Research Group, 1993). This expansion contributes to the formation of an aberrant and misfolded protein that has been associated with aggregation and toxicity (Labbadia & Morimoto, 2013), both of which are mechanisms that have been implicated in multiple neurological disorders. In addition, although this mutation is ubiquitous in all cells of the body, selective vulnerability has been described on the part of medium-sized spinous neurons (MSNs) located in the striatum nucleus, formed by the caudate and putamen in humans (Vonsattel et al., 1985). These striatal MSNs can be classified into two types depending on the receptors they express and the brain areas they project to (Gerfen et al., 1990), forming the direct and indirect pathways of the basal ganglia. The correct balance of signaling between these pathways is what allows the voluntary control of movements, so that striatal atrophy, preferably of the indirect pathway at the beginning, during the progression of the disease leads to an alteration in the circuits giving rise to the motor symptoms characteristic of HD (Albin et al., 1989). To date, most of the research on the molecular mechanisms involved in the pathophysiology of HD has focused on the alterations caused by the mutated protein (Zuccato et al., 2010). However, in recent years, it has been observed that the toxicity generated by the mutated protein coexists with RNA-mediated pathogenic mechanisms, which can be subdivided into those associated with expanded RNA with CAG repeats and those related to other non-coding RNAs. On the one hand, it has been observed that RNA with CAG triplet expansion can exert its toxicity through multiple mechanisms (Heinz et al., 2021; Malik et al., 2021; Martí, 2016). Among them, we find the formation of short-sized RNAs (21 nt) with CAG repeats (sCAG) through Dicer, whose levels are dependent on the length of triplet expansion (Bañez-Coronel et al., 2012). These species have gene silencing capacity in such a way that they have been associated with transcriptomic alterations and can affect neuronal viability per se (Bañez-Coronel et al., 2012). In addition, our group has also described that its effects can be partially reversed with the use of a modified antisense oligonucleotide, targeting CAG repeats (LNA-CTG), producing a recovery of motor function and levels of multiple striatal markers in a murine model of HD (Rué et al., 2016). On the other hand, in recent years, different mechanisms of RNA toxicity involving multiple biotypes of non-coding RNAs have also been described sRNA, <200 nt), such as microRNAs (miRNA), ribosomal RNAs (rRNA) or transfer RNAs (tRNAs), which have also been clearly associated with the regulation of gene expression, among many other functions (Cech & Steitz, 2014). At the same time, it has been observed that in the context of HD there is significant transcriptomic dysregulation in different brain regions (Martí et al., 2010), pointing to a possible role of sRNAs in the pathophysiology of HD. In addition, although the canonical function described by tRNAs is based on allowing the synthesis of proteins in the ribosome by decoding information at the mRNA level, implications of tRNAs in other biological processes such as cell signaling and survival, apoptosis, amino acid metabolism or even in stress response programs have also been described (Raina & Ibba, 2014). Specifically, many of these functions have been attributed to fragments derived from these tRNAs (tsRNAs), some of which are constitutive components of all cells, while others only occur in situations of cellular stress (Anderson & Ivanov, 2014) and have been related to different pathological situations such as cancers, infections and different paradigms of neurodegeneration (R. Magee & Rigoutsos, 2020). Based on the bibliographic information presented, our hypothesis is that the pathogenic mechanisms caused by RNA, and specifically sRNA, are much more involved than previously thought in HD and that their study becomes of high importance both to understand the pathophysiological bases of HD and to develop new therapies. Therefore, the main objective of this project was to identify new species of sRNA involved in the pathogenic mechanisms of HD and determine their contribution to the alterations characteristic of this pathology. |
|---|