Dataset Information

Structural and molecular myelination deficits occur prior to neuronal loss in the YAC128 and BACHD models of Huntington disease.

ABSTRACT: White matter (WM) atrophy is a significant feature of Huntington disease (HD), although its aetiology and early pathological manifestations remain poorly defined. In this study, we aimed to characterize WM-related features in the transgenic YAC128 and BACHD models of HD. Using diffusion tensor magnetic resonance imaging (DT-MRI), we demonstrate that microstructural WM abnormalities occur from an early age in YAC128 mice. Similarly, electron microscopy analysis of myelinated fibres of the corpus callosum indicated that myelin sheaths are thinner in YAC128 mice as early as 1.5 months of age, well before any neuronal loss can be detected. Transcript levels of myelin-related genes in striatal and cortical tissues were significantly lower in YAC128 mice from 2 weeks of age, and these findings were replicated in differentiated primary oligodendrocytes from YAC128 mice, suggesting a possible mechanistic explanation for the observed structural deficits. Concordant with these observations, we demonstrate reduced expression of myelin-related genes at 3 months of age and WM microstructural abnormalities using DT-MRI at 12 months of age in the BACHD rats. These findings indicate that WM deficits in HD are an early phenotype associated with cell-intrinsic effects of mutant huntingtin on myelin-related transcripts in oligodendrocytes, and raise the possibility that WM abnormalities may be an early contributing factor to the pathogenesis of HD.

SUBMITTER: Teo RT

PROVIDER: S-EPMC5181633 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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Structural and molecular myelination deficits occur prior to neuronal loss in the YAC128 and BACHD models of Huntington disease.

Teo Roy Tang Yi RT Hong Xin X Yu-Taeger Libo L Huang Yihui Y Tan Liang Juin LJ Xie Yuanyun Y To Xuan Vinh XV Guo Ling L Rajendran Reshmi R Novati Arianna A Calaminus Carsten C Riess Olaf O Hayden Michael R MR Nguyen Huu P HP Chuang Kai-Hsiang KH Pouladi Mahmoud A MA

Human molecular genetics 20160428 13

White matter (WM) atrophy is a significant feature of Huntington disease (HD), although its aetiology and early pathological manifestations remain poorly defined. In this study, we aimed to characterize WM-related features in the transgenic YAC128 and BACHD models of HD. Using diffusion tensor magnetic resonance imaging (DT-MRI), we demonstrate that microstructural WM abnormalities occur from an early age in YAC128 mice. Similarly, electron microscopy analysis of myelinated fibres of the corpus ...[more]

PMID: 27126634

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Project description:Huntington disease (HD) is an autosomal dominantly inherited, progressive neurodegenerative disorder which is accompanied by executive dysfunctions and emotional alteration. The aim of the present study was to assess the impact of emotion/stress on on-going highly demanding cognitive tasks, i.e., temporal processing, as a function of age in BACHD rats (a "full length" model of HD). Middle-aged (4-6 months) and old (10-12 months) rats were first trained on a 2 vs. 8-s temporal discrimination task, and then exposed to a series of bisection tests under normal and stressful (10 mild unpredictable foot-shocks) conditions. The animals were then trained on a peak interval task, in which reinforced fixed-interval (FI) 30-s trials were randomly intermixed with non-reinforced probe trials. After training, the effect of stress upon time perception was again assessed. Sensitivity to foot-shocks was also assessed independently. The results show effects of both age and genotype, with largely greater effects in old BACHD animals. The older BACHD animals had impaired learning in both tasks, but reached equivalent levels of performance as WT animals at the end of training in the temporal discrimination task, while remaining impaired in the peak interval task. Whereas sensitivity to foot-shock did not differ between BACHD and WT rats, delivery of foot-shocks during the test sessions had a disruptive impact on temporal behavior in WT animals, an effect which increased with age. In contrast, BACHD rats, independent of age, did not show any significant disruption under stress. In conclusion, BACHD rats showed a disruption in temporal learning in late symptomatic animals. Age-related modification in stress-induced impairment of temporal control of behavior was also observed, an effect which was greatly reduced in BACHD animals, thus confirming previous results suggesting reduced emotional reactivity in HD animals. The results suggest a staggered onset in cognitive and emotional alterations in HD, with emotional alteration being the earliest, possibly related to different time courses of degeneration in cortico-striatal and amygdala circuits.

Project description:Genetic variants that define two distinct haplotypes at the TMEM106B locus have been implicated in multiple neurodegenerative diseases and in healthy brain ageing. In frontotemporal dementia (FTD), the high expressing TMEM106B risk haplotype was shown to increase susceptibility for FTD with TDP-43 inclusions (FTD-TDP) and to modify disease penetrance in progranulin mutation carriers (FTD-GRN). To elucidate the biological function of TMEM106B and determine whether lowering TMEM106B may be a viable therapeutic strategy, we performed brain transcriptomic analyses in 8-month-old animals from our recently developed Tmem106b-/- mouse model. We included 10 Tmem106b+/+ (wild-type), 10 Tmem106b+/- and 10 Tmem106-/- mice. The most differentially expressed genes (153 downregulated and 60 upregulated) were identified between Tmem106b-/- and wild-type animals, with an enrichment for genes implicated in myelination-related cellular processes including axon ensheathment and oligodendrocyte differentiation. Co-expression analysis also revealed that the most downregulated group of correlated genes was enriched for myelination-related processes. We further detected a significant loss of OLIG2-positive cells in the corpus callosum of Tmem106b-/- mice, which was present already in young animals (21 days) and persisted until old age (23 months), without worsening. Quantitative polymerase chain reaction revealed a reduction of differentiated but not undifferentiated oligodendrocytes cellular markers. While no obvious changes in myelin were observed at the ultrastructure levels in unchallenged animals, treatment with cuprizone revealed that Tmem106b-/- mice are more susceptible to cuprizone-induced demyelination and have a reduced capacity to remyelinate, a finding which we were able to replicate in a newly generated Tmem106b CRISPR/cas9 knock-out mouse model. Finally, using a TMEM106B HeLa knock-out cell line and primary cultured oligodendrocytes, we determined that loss of TMEM106B leads to abnormalities in the distribution of lysosomes and PLP1. Together these findings reveal an important function for TMEM106B in myelination with possible consequences for therapeutic strategies aimed at lowering TMEM106B levels.

Project description:Genetic variants that define two distinct haplotypes at the TMEM106B locus have been implicated in multiple neurodegenerative diseases and in healthy brain aging. In frontotemporal dementia (FTD), the high expressing TMEM106B risk haplotype was shown to increase susceptibility for FTD with TDP-43 inclusions (FTD-TDP) and to modify disease penetrance in progranulin mutation carriers (FTD-GRN). To further elucidate the biological function of TMEM106B and determine whether lowering TMEM106B may be a viable therapeutic strategy, we performed brain transcriptomic analyses in 8-month-old animals from our recently developed Tmem106b-/- mouse model. We included 10 Tmem106b+/+ (WT), 10 Tmem106b+/- and 10 Tmem106-/- mice. The most differentially expressed genes (153 down-regulated and 60 upregulated) were identified between Tmem106b-/- and WT animals, with an enrichment for genes implicated in myelination-related cellular processes including axon ensheathment and oligodendrocyte differentiation. Co-expression analysis also revealed that the most downregulated group of correlated genes was enriched for myelination-related processes. We further detected a significant loss of Olig2-positive cells in the corpus callosum of Tmem106b-/- mice, which was present already in young animals (21 days) and persisted until old age (23 months), without worsening. qPCR revealed a reduction of differentiated but not undifferentiated oligodendrocytes cellular markers. While no obvious changes in myelin were observed at the ultrastructure levels in unchallenged animals, treatment with cuprizone revealed that Tmem106b-/- mice are more susceptible to cuprizone-induced de-myelination and have a reduced capacity to re-myelinate, a finding which we were able to replicate in a newly generated Tmem106b CRISPR/cas9 knock-out mouse model. Finally, using a TMEM106B HeLa knock-out cell line, we determined that loss of TMEM106B leads to abnormalities in the distribution of lysosomes and PLP1 trafficking but not to differences in MOG trafficking which is lysosome-independent. Together these findings reveal an important function for TMEM106B in myelination with possible consequences for therapeutic strategies aimed at lowering TMEM106B levels.

Dataset Information

Structural and molecular myelination deficits occur prior to neuronal loss in the YAC128 and BACHD models of Huntington disease.

Publications

Structural and molecular myelination deficits occur prior to neuronal loss in the YAC128 and BACHD models of Huntington disease.

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