Identification of the key role of white matter alteration in the pathogenesis of Huntington’s Disease

Pérot, J.; Célestine, Marina; Palombo, Marco; Dhénain, Marc; Humbert, Sandrine; Brouillet, Emmanuel; Flament, Julien

doi:10.1101/2021.06.21.449242

Cited by 3 publications

(3 citation statements)

References 93 publications

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“…To further demonstrate JAK2ca beneficial effects on clinically-relevant pathological outcomes, we next performed magnetic resonance imaging. Eighteen month-old heterozygous Hdh140 mice display significant striatal atrophy 46 , likely due to the atrophy of striatal neurons themselves 47 , and not to their death, as neuronal loss was described only in older homozygous Hdh140 mice 43 . Striatal volume can be measured accurately with T 2 -weighted magnetic resonance imaging 48 , and striatal atrophy is observed at prodromal stages in Huntington's disease patients 49 .…”

Section: Activation Of Jak2-stat3 Pathway In Astrocytes Is Beneficial...mentioning

confidence: 95%

Reactive astrocytes promote proteostasis in Huntington’s disease through the JAK2-STAT3 pathway

Abjean

Haim

Riquelme-Pérez

et al. 2022

Brain

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Huntington’s disease is a fatal neurodegenerative disease characterized by striatal neurodegeneration, aggregation of mutant Huntingtin and the presence of reactive astrocytes. Astrocytes are important partners for neurons and engage in a specific reactive response in Huntington’s disease that involves morphological, molecular and functional changes. How reactive astrocytes contribute to Huntington’s disease is still an open question, especially because their reactive state is poorly reproduced in experimental mouse models. Here, we show that the JAK2-STAT3 pathway, a central cascade controlling astrocyte reactive response, is activated in the putamen of Huntington’s disease patients. Selective activation of this cascade in astrocytes through viral gene transfer reduces the number and size of mutant Huntingtin aggregates in neurons and improves neuronal defects in two complementary mouse models of Huntington’s disease. It also reduces striatal atrophy and increases glutamate levels, two central clinical outcomes measured by non-invasive magnetic resonance imaging. Moreover, astrocyte-specific transcriptomic analysis shows that activation of the JAK2-STAT3 pathway in astrocytes coordinates a transcriptional program that increases their intrinsic proteolytic capacity, through the lysosomal and ubiquitin-proteasome degradation systems. This pathway also enhances their production and exosomal release of the co-chaperone DNAJB1, which contributes to mutant Huntingtin clearance in neurons. Together, our results show that the JAK2-STAT3 pathway controls a beneficial proteostasis response in reactive astrocytes in Huntington’s disease, which involves bi-directional signalling with neurons to reduce mutant Huntingtin aggregation, eventually improving disease outcomes.

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Section: Activation Of Jak2-stat3 Pathway In Astrocytes Is Beneficial...mentioning

confidence: 95%

Reactive astrocytes promote proteostasis in Huntington’s disease through the JAK2-STAT3 pathway

Abjean

Haim

Riquelme-Pérez

et al. 2022

Brain

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“…Perot et al reported that there was no variation of corpus callosum volume in the CAG140KI mice by using DTI assay, which showed that FA values in CAG140KI mice are only reduced in the first 8 months compared to WT. This difference becomes rather insignificant over time [ 55 ]. Others also reported the absence of white matter changes in the Hdh (CAG) 150 mouse brain using MRI study [ 56 ].…”

Section: Evidence Of White Matter Defects In Mouse Modelsmentioning

confidence: 99%

Insights into White Matter Defect in Huntington’s Disease

Sun

Tong

Yang

et al. 2022

Cells

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Huntington’s disease (HD) is an autosomal-dominant inherited progressive neurodegenerative disorder. It is caused by a CAG repeat expansion in the Huntingtin gene that is translated to an expanded polyglutamine (PolyQ) repeat in huntingtin protein. HD is characterized by mood swings, involuntary movement, and cognitive decline in the late disease stage. HD patients often die 15–20 years after disease onset. Currently, there is no cure for HD. Due to the striking neuronal loss in HD, most studies focused on the investigation of the predominantly neuronal degeneration in specific brain regions. However, the pathology of the white matter area in the brains of HD patients was also reported by clinical imaging studies, which showed white matter abnormalities even before the clinical onset of HD. Since oligodendrocytes form myelin sheaths around the axons in the brain, white matter lesions are likely attributed to alterations in myelin and oligodendrocyte-associated changes in HD. In this review, we summarized the evidence for white matter, myelin, and oligodendrocytes alterations that were previously observed in HD patients and animal models. We also discussed potential mechanisms for white matter changes and possible treatment to prevent glial dysfunction in HD.

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“…Images were co-registered and automatically segmented using an in-house python library Sammba-MRI [ 17 ], as already described [ 18 ]. Metabolites concentration were estimated with LCModel [ 19 ] using default pipeline, and was normalized by total creatine (tCr).…”

Section: Methodsmentioning

confidence: 99%

Longitudinal MRI and 1H-MRS study of SCA7 mouse forebrain reveals progressive multiregional atrophy and early brain metabolite changes indicating early neuronal and glial dysfunction

Pérot,

Niewiadomska-Cimicka,

Brouillet

et al. 2024

PLoS ONE

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SpinoCerebellar Ataxia type 7 (SCA7) is an inherited disorder caused by CAG triplet repeats encoding polyglutamine expansion in the ATXN7 protein, which is part of the transcriptional coactivator complex SAGA. The mutation primarily causes neurodegeneration in the cerebellum and retina, as well as several forebrain structures. The SCA7140Q/5Q knock-in mouse model recapitulates key disease features, including loss of vision and motor performance. To characterize the temporal progression of brain degeneration of this model, we performed a longitudinal study spanning from early to late symptomatic stages using high-resolution magnetic resonance imaging (MRI) and in vivo 1H-magnetic resonance spectroscopy (1H-MRS). Compared to wild-type mouse littermates, MRI analysis of SCA7 mice shows progressive atrophy of defined brain structures, with the striatum, thalamus and cortex being the first and most severely affected. The volume loss of these structures coincided with increased motor impairments in SCA7 mice, suggesting an alteration of the sensory-motor network, as observed in SCA7 patients. MRI also reveals atrophy of the hippocampus and anterior commissure at mid-symptomatic stage and the midbrain and brain stem at late stage. 1H-MRS of hippocampus, a brain region previously shown to be dysfunctional in patients, reveals early and progressive metabolic alterations in SCA7 mice. Interestingly, abnormal glutamine accumulation precedes the hippocampal atrophy and the reduction in myo-inositol and total N-acetyl-aspartate concentrations, two markers of glial and neuronal damage, respectively. Together, our results indicate that non-cerebellar alterations and glial and neuronal metabolic impairments may play a crucial role in the development of SCA7 mouse pathology, particularly at early stages of the disease. Degenerative features of forebrain structures in SCA7 mice correspond to current observations made in patients. Our study thus provides potential biomarkers that could be used for the evaluation of future therapeutic trials using the SCA7140Q/5Q model.

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Identification of the key role of white matter alteration in the pathogenesis of Huntington’s Disease

Cited by 3 publications

References 93 publications

Reactive astrocytes promote proteostasis in Huntington’s disease through the JAK2-STAT3 pathway

Reactive astrocytes promote proteostasis in Huntington’s disease through the JAK2-STAT3 pathway

Insights into White Matter Defect in Huntington’s Disease

Longitudinal MRI and 1H-MRS study of SCA7 mouse forebrain reveals progressive multiregional atrophy and early brain metabolite changes indicating early neuronal and glial dysfunction

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