Dysregulation of long non‐coding RNAs and their mechanisms in Huntington's disease

Abstract

Extensive alterations in gene regulatory networks are a typical characteristic of Huntington's disease (HD); these include alterations in protein‐coding genes and poorly understood non‐coding RNAs (ncRNAs), which are associated with pathology caused by mutant huntingtin. Long non‐coding RNAs (lncRNAs) are an important class of ncRNAs involved in a variety of biological functions, including transcriptional regulation and post‐transcriptional modification of many targets, and likely contributed to the pathogenesis of HD. While a number of changes in lncRNAs expression have been observed in HD, little is currently known about their functions. Here, we discuss their possible mechanisms and molecular functions, with a particular focus on their roles in transcriptional regulation. These findings give us a better insight into HD pathogenesis and may provide new targets for the treatment of this neurodegenerative disease.

Regulation of Oxidative Stress by Long Non-coding RNAs in Central Nervous System Disorders

“…LncRNAs have differences in size, molecular partners, and mechanism of action. According to their relative position and host protein-coding genes, lncRNAs can be divided into exons, introns, overlapping lncRNAs, and intergenic lncRNAs ( Figure 2 ; Tan et al, 2021 ).…”

Long Intergenic Noncoding RNAs Affect Biological Pathways Underlying Autoimmune and Neurodegenerative Disorders

“…The polyQ tract is responsible for the toxic gain of function and aggregation of mutant Huntingtin (mHTT) protein, leading to neuronal dysfunction and loss. The major and earliest site of pathology is the striatum, with medium spiny neurons the most vulnerable cells in HD; however, other regions of the brain, such as the cortex and cerebellum, are also affected [ 68 ].…”

“…Its overexpression and negative effect on proapoptotic PRDM5 (PR/SET Domain 5) was shown to inhibit neuronal apoptosis and alleviate acute spinal cord injury in a rat model [ 70 ], suggesting a potential neuroprotective role of DGCR5 in the neurodegeneration in HD. In turn, human accelerated region 1 is a conserved genomic region transcribed into a cis -antisense pair of structured lincRNAs, HAR1F and HAR1R , which are specifically expressed in developing cortical neurons [ 68 ]. Global ChIP-seq analysis identified HAR1 as a REST target and, consistent with this finding, showed that both HAR1F and HAR1R are significantly downregulated in the striatum of HD patients [ 69 ].…”

“…In this study, simultaneous knockdown of MEG3 and exogenous expression of N-terminal HTT with 83 glutamines resulted in reduced formation of mHTT aggregates and decreased expression of the p53 transcription factor, which is known to be bound and stabilized by MEG3 [ 110 ]. Moreover, the documented role of MEG3 as the PRC2 interactor and its functions in the cAMP-dependent signaling pathway and cell proliferation strongly support its involvement in the massive transcriptional abnormalities observed in HD [ 68 ]. MEG3 expression was also found to be decreased in the plasma of PD patients and in a cellular model, and this downregulation is related to the aggravation of nonmotor symptoms, cognitive decline, and PD stage [ 159 ].…”

The emerging role of long non-coding RNAs, microRNAs, and an accelerated epigenetic age in Huntington’s disease

“…Non-coding RNAs have been found to affect the pathobiology of HD or mediate the effects of trinucleotide expansion in its pathophysiology ( Dubois et al, 2021 ; Tan et al, 2021 ). Particularly, two classes of non-coding RNAs, namely microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) have been verified to be abnormally expressed in HD ( Johnson, 2012 ; Dong and Cong, 2021b ; Tan et al, 2021 ). These two classes of non-coding RNAs have been classified based on their size using the cutoff value of 200 nt.…”