ABSTRACT
Huntingtin protein, mutated in Huntington's disease, is implicated in nucleic acid-mediated processes, yet the evidence for direct huntingtin-nucleic acid interaction is limited. Here, we show wild-type and mutant huntingtin copurify with nucleic acids, primarily RNA, and interact directly with G-rich RNAs in in vitro assays. Huntingtin RNA-immunoprecipitation sequencing from patient-derived fibroblasts and neuronal progenitor cells expressing wild-type and mutant huntingtin revealed long noncoding RNA NEAT1 as a significantly enriched transcript. Altered NEAT1 levels were evident in Huntington's disease cells and postmortem brain tissues, and huntingtin knockdown decreased NEAT1 levels. Huntingtin colocalized with NEAT1 in paraspeckles, and we identified a high-affinity RNA motif preferred by huntingtin. This study highlights NEAT1 as a huntingtin interactor, demonstrating huntingtin's involvement in RNA-mediated functions and paraspeckle regulation.
Subject(s)
Huntingtin Protein , Huntington Disease , RNA, Long Noncoding , RNA-Binding Proteins , Humans , Huntingtin Protein/metabolism , Huntingtin Protein/genetics , RNA, Long Noncoding/metabolism , RNA, Long Noncoding/genetics , RNA-Binding Proteins/metabolism , RNA-Binding Proteins/genetics , Huntington Disease/metabolism , Huntington Disease/genetics , Huntington Disease/pathology , Protein Binding , Fibroblasts/metabolism , MutationABSTRACT
Structural and molecular myelination deficits represent early pathological features of Huntington disease (HD). Recent evidence from germ-free (GF) animals suggests a role for microbiota-gut-brain bidirectional communication in the regulation of myelination. In this study, we aimed to investigate the impact of microbiota on myelin plasticity and oligodendroglial population dynamics in the mixed-sex BACHD mouse model of HD. Ultrastructural analysis of myelin in the corpus callosum revealed alterations of myelin thickness in BACHD GF compared to specific-pathogen free (SPF) mice, whereas no differences were observed between wild-type (WT) groups. In contrast, myelin compaction was altered in all groups when compared to WT SPF animals. Levels of myelin-related proteins were generally reduced, and the number of mature oligodendrocytes was decreased in the prefrontal cortex under GF compared to SPF conditions, regardless of genotype. Minor differences in commensal bacteria at the family and genera levels were found in the gut microbiota of BACHD and WT animals housed in standard living conditions. Our findings indicate complex effects of a germ-free status on myelin-related characteristics, and highlight the adaptive properties of myelination as a result of environmental manipulation.
Subject(s)
Huntington Disease/microbiology , Myelin Proteins/metabolism , Myelin Sheath/pathology , White Matter/microbiology , Animals , Bacteria/isolation & purification , Corpus Callosum/metabolism , Corpus Callosum/microbiology , Disease Models, Animal , Huntington Disease/pathology , Mice, Transgenic , Myelin Sheath/metabolism , Neuronal Plasticity/physiology , Oligodendroglia/metabolism , Prefrontal Cortex/metabolism , White Matter/pathologyABSTRACT
Structural and molecular myelination deficits represent early pathological features of Huntington disease (HD). Recent evidence from germ-free (GF) animals suggests a role for microbiota-gut-brain bidirectional communication in the regulation of myelination. In this study, we aimed to investigate the impact of microbiota on myelin plasticity and oligodendroglial population dynamics in the mixed-sex BACHD mouse model of HD. Ultrastructural analysis of myelin in the corpus callosum revealed alterations of myelin thickness in BACHD GF compared to specific-pathogen free (SPF) mice, whereas no differences were observed between wild-type (WT) groups. In contrast, myelin compaction was altered in all groups when compared to WT SPF animals. Levels of myelin-related proteins were generally reduced, and the number of mature oligodendrocytes was decreased in the prefrontal cortex under GF compared to SPF conditions, regardless of genotype. Minor differences in commensal bacteria at the family and genera levels were found in the gut microbiota of BACHD and WT animals housed in standard living conditions. Our findings indicate complex effects of a germ-free status on myelin-related characteristics, and highlight the adaptive properties of myelination as a result of environmental manipulation.