<i>SREBP2</i> gene therapy targeting striatal astrocytes ameliorates Huntington’s disease phenotypes

Birolini, Giulia; Verlengia, Gianluca; Talpo, Francesca; Maniezzi, Claudia; Zentilin, Lorena; Giacca, Mauro; Conforti, Paola; Cordiglieri, Chiara; Caccia, Claudio; Leoni, Valerio; Taroni, Franco; Biella, Gerardo; Simonato, Michele; Cattaneo, Elena; Valenza, Marta

doi:10.1093/brain/awab186

Cited by 22 publications

(42 citation statements)

References 69 publications

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“…Expanding on the feature of mHTT-induced neuropathology and loss of normal HTT function (here modeled by the wtHTT 18Q vector construct), alterations in cholesterol and FA metabolism that provide the main components of the myelin sheath and precursors of steroid hormones [60] are also found in HD [61][62][63]. Strategies of cholesterol delivery to the HD brain and targeting the key components Sterol-regulatory element-binding protein 2 (SREBP-2) and Sirtuin 2 (SIRT2) in the striatum can ameliorate disease phenotypes [64][65][66]. Here we found that Stoml3, present in cholesterol-rich lipid rafts and associated with dopaminergic transmission [67], was differentially downregulated in 79Q vs. WT and trended towards downregulation in 18Q vs. WT (p < 0.05 but adj p > 0.05).…”

Section: Discussionmentioning

confidence: 99%

Microarray profiling of hypothalamic gene expression changes in Huntington’s disease mouse models

Dickson

Dwijesha

Andersson

et al. 2022

Preprint

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Structural changes and neuropathology in the hypothalamus have been suggested to contribute to the non-motor manifestations of Huntington's disease (HD), a neurodegenerative disorder caused by an expanded CAG repeat in the huntingtin (HTT) gene. In the present study, we investigated whether transcriptional changes would be part of hypothalamic pathology induced by the disease-causing huntingtin (HTT) protein. We performed microarray analysis using the Affymetrix platform on total hypothalamic RNA isolated from two HD mouse models and their littermate controls; BACHD mice with ubiquitous expression of full-length mutant HTT (mHTT) and wild-type mice with targeted hypothalamic overexpression of either wild-type HTT (wtHTT) or mHTT fragments. To analyze microarray datasets (34760 variables) and obtain functional implications of differential expression patterns, we used Linear Models for Microarray Data (limma) followed by Gene Set Enrichment Analysis (GSEA) using ClusterProfiler. Limma identified 735 and 721 significantly differentially expressed genes (adjusted p < 0.05) in hypothalamus of AAV datasets wtHTT vs control and mHTT vs control. In contrast, for BACHD datasets and the AAV mHTT vs. wtHTT dataset, none of the genes were differentially expressed (adjusted p-value > 0.05 for all probe IDs). In AAV groups, from the combined limma with GSEA using ClusterProfiler, we found both shared and unique gene sets and pathways for mice with wtHTT overexpression compared to mice with mHTT overexpression. mHTT caused widespread suppression of neuroendocrine networks, as evident by GSEA enrichment of GO-terms related to neurons and/or specific neuroendocrine populations. Using qRT-PCR, we confirmed that mHTT overexpression caused significant downregulation of key enzymes involved in neuropeptide synthesis, including histidine and dopa decarboxylases, compared to wtHTT overexpression. Multiple biosynthetic pathways such as sterol synthesis were among the top shared processes, where both unique and shared genes constituted leading-edge subsets. In conclusion, mice with targeted overexpression of HTT (wtHTT or mHTT) in the hypothalamus show dysregulation of pathways, of which there are subsets of shared pathways and pathways unique to either wtHTT or mHTT overexpression.

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Section: Discussionmentioning

confidence: 99%

Microarray profiling of hypothalamic gene expression changes in Huntington’s disease mouse models

Dickson

Dwijesha

Andersson

et al. 2022

Preprint

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“…However, this compound failed in a phase 3 clinical trial for ALS 35 , which could underlie the requirement for a concomitant therapy that compensates for cholesterol in ALS MNs. Furthermore, as shown in Huntington’s disease, SREBP2 gene therapy may be promising for ALS 36 . Taken together, this reverse-translational study could provide a molecular basis for future ALS therapy targeting cholesterol biosynthesis.…”

Section: Discussionmentioning

confidence: 94%

TDP-43 regulates cholesterol biosynthesis by inhibiting sterol regulatory element-binding protein 2

Egawa

Izumi

Suzuki

et al. 2022

Sci Rep

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Dyslipidemia is considered an essential component of the pathological process of amyotrophic lateral sclerosis (ALS), a fatal motor neuron disease. Although TAR DNA Binding Protein 43 kDa (TDP-43) links both familial and sporadic forms of ALS and cytoplasmic aggregates are a hallmark of most cases of ALS, the molecular mechanism and the in vivo relation of ALS dyslipidemia with TDP-43 have been unclear. To analyze the dyslipidemia-related gene expression by TDP-43, we performed expression microarray and RNA deep sequencing (RNA-Seq) using cell lines expressing high levels of TDP-43 and identified 434 significantly altered genes including sterol regulatory element-binding protein 2 (SREBP2), a master regulator of cholesterol homeostasis and its downstream genes. Elevated TDP-43 impaired SREBP2 transcriptional activity, leading to inhibition of cholesterol biosynthesis. The amount of cholesterol was significantly decreased in the spinal cords of TDP-43-overexpressed ALS model mice and in the cerebrospinal fluids of ALS patients. These results suggested that TDP-43 could play an essential role in cholesterol biosynthesis in relation to ALS dyslipidemia.

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“…SREBP2 is expressed in glial cells, especially in astrocytes and oligodendrocytes, where it controls lipid synthesis ( Camargo et al, 2009 ). Mutant HTT decreases the activity of SREBP2 by 50% in cells and mouse brain tissues ( Valenza et al, 2005 ), and overexpression of its active form in astrocytes, in vitro and in vivo in R6/2 mice, showed beneficial effects in neurons ( Valenza et al, 2015b ; Birolini et al, 2021b ). This suggests an important dialogue between glial and neuronal cells for proper cholesterol homeostasis.…”

Section: Clinical Strategies To Manipulate Cholesterol Metabolism In ...mentioning

confidence: 99%

“…This suggests an important dialogue between glial and neuronal cells for proper cholesterol homeostasis. In this way, in an elegant study, a gene therapy approach was used to express the transcriptionally active form of human SREBP2 specifically in striatal astrocytes of R6/2 mice ( Birolini et al, 2021b ). The authors found a re-activation of the cholesterol pathway biosynthesis, associated with restoration of synaptic transmission, clearance of mHTT aggregates, and improvement of motor defects and cognitive decline.…”

Section: Clinical Strategies To Manipulate Cholesterol Metabolism In ...mentioning

confidence: 99%

Altered Cholesterol Homeostasis in Huntington’s Disease

Kacher

Mounier

Caboche

et al. 2022

Front. Aging Neurosci.

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Huntington’s disease (HD) is an autosomal dominant genetic disorder caused by an expansion of the CAG repeat in the first exon of Huntingtin’s gene. The associated neurodegeneration mainly affects the striatum and the cortex at early stages and progressively spreads to other brain structures. Targeting HD at its earlier stages is under intense investigation. Numerous drugs were tested, with a rate of success of only 3.5% approved molecules used as symptomatic treatment. The restoration of cholesterol metabolism, which is central to the brain homeostasis and strongly altered in HD, could be an interesting disease-modifying strategy. Cholesterol is an essential membrane component in the central nervous system (CNS); alterations of its homeostasis have deleterious consequences on neuronal functions. The levels of several sterols, upstream of cholesterol, are markedly decreased within the striatum of HD mouse model. Transcription of cholesterol biosynthetic genes is reduced in HD cell and mouse models as well as post-mortem striatal and cortical tissues from HD patients. Since the dynamic of brain cholesterol metabolism is complex, it is essential to establish the best method to target it in HD. Cholesterol, which does not cross the blood-brain-barrier, is locally synthesized and renewed within the brain. All cell types in the CNS synthesize cholesterol during development but as they progress through adulthood, neurons down-regulate their cholesterol synthesis and turn to astrocytes for their full supply. Cellular levels of cholesterol reflect the dynamic balance between synthesis, uptake and export, all integrated into the context of the cross talk between neurons and glial cells. In this review, we describe the latest advances regarding the role of cholesterol deregulation in neuronal functions and how this could be a determinant factor in neuronal degeneration and HD progression. The pathways and major mechanisms by which cholesterol and sterols are regulated in the CNS will be described. From this overview, we discuss the main clinical strategies for manipulating cholesterol metabolism in the CNS, and how to reinstate a proper balance in HD.

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SREBP2 gene therapy targeting striatal astrocytes ameliorates Huntington’s disease phenotypes

Cited by 22 publications

References 69 publications

Microarray profiling of hypothalamic gene expression changes in Huntington’s disease mouse models

Microarray profiling of hypothalamic gene expression changes in Huntington’s disease mouse models

TDP-43 regulates cholesterol biosynthesis by inhibiting sterol regulatory element-binding protein 2

Altered Cholesterol Homeostasis in Huntington’s Disease

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