A Fresh Look at Huntingtin mRNA Processing in Huntington’s Disease

Abstract

Huntington’s disease (HD) is an inherited neurodegenerative disorder caused by a mutation that expands the polyglutamine (CAG) repeat in exon 1 of the huntingtin (HTT) gene. Wild-type HTT protein interacts with other proteins to protect cells against toxic stimuli, mediate vesicle transport and endocytosis, and modulate synaptic activity. Mutant HTT protein disrupts autophagy, vesicle transport, neurotransmitter signaling, and mitochondrial function. Although many of the activities of wild-type HTT protein and the toxicities of mutant HTT protein are characterized, less is known about the activities of HTT mRNA. Most putative HD therapies aim to target mutant HTT mRNA before it is translated into the protein. Therefore, it is imperative to learn as much as we can about how cells handle both wild-type and mutant HTT mRNA so that effective therapies can be designed. Here, we review the structure of wild-type and mutant HTT mRNA, with emphasis on their alternatively polyadenylated or spliced isoforms. We then consider the abundance of HTT mRNA isoforms in HD and discuss the potential implications of these findings. Evidence in the review should be used to guide future research aimed at developing mRNA-lowering therapies for HD.

Non-Cell Autonomous and Epigenetic Mechanisms of Huntington’s Disease

“…posttranslational modifications [258], proteostasis [259], autophagy [260,261], redox homeostasis [262], metabolism [263,264], HTT mRNA [265,266], Ca 2+ and dopamine signaling [61], inflammation [267], in vitro modelling of HD [268,269], striatal neurogenesis [270], stem cell treatment [271][272][273][274][275][276][277][278][279], electric stimulation therapy [280], network connectivity in presymptomatic HD brain [281], non-motor symptoms [282], gut microbiome [283], human immunodeficiency virus [284], diagnosis [285,286], clinical progression [287], treatment for the symptoms [288], physical therapy [289], psychological interventions [290,291], and management of agitation [292]. Collectively, the previous studies have potential to reveal spatiotemporal and cell-type specific mechanism of HD pathology.…”

Comparison of the Huntington's Disease like 2 and Huntington's Disease Clinical Phenotypes

“…Current evidence suggests that the HD expansion mutation results in disease primarily through the expression of a protein with an excessively long stretch of polyglutamine residues, with contributions from toxic properties of the mutant RNA and loss of normal protein function . In HDL2, in which pathogenic pathways are less established, evidence suggests that loss of JPH3 expression and toxic properties of the mutant JPH3 RNA contribute to neurodegeneration, with a role for cryptic antisense expression of a transcript encoding a protein with an expanded stretch of polyglutamine residues .…”

“…Current evidence suggests that the HD expansion mutation results in disease primarily through the expression of a protein with an excessively long stretch of polyglutamine residues, with contributions from toxic properties of the mutant RNA and loss of normal protein function. 30 In HDL2, in which pathogenic pathways are less established, evidence suggests that loss of JPH3 expression and toxic properties of the mutant JPH3 RNA contribute to neurodegeneration, with a role for cryptic antisense expression of a transcript encoding a protein with an expanded stretch of polyglutamine residues. 29,31,32 The similarities between the two diseases genetically, clinically, pathologically, and radiologically, However, it is likely that divergent aspects of their pathogenesis result in subtle phenotypic differences like dysarthria and dystonia, or more striking symptoms at onset, leading to an earlier diagnosis.…”

Huntingtin Lowering Strategies

“…Splice variants and Repeat Associated Non-AUG (RAN) translation can also lead to neurotoxic isoforms of htt [15]. In addition, there is increasing evidence that a pathologically prolonged htt mRNA leads to defective binding of RNA binding proteins, further contributing to pathogenesis (overview in [15]) ( Figure 1B). Prolonged htt protein acts primarily through a toxic gain-of-function, interfering with autophagy, vesicle transport, neurotransmitter release and mitochondrial function ( Figure 1C).…”