Atxn2-CAG100-KnockIn mouse spinal cord shows progressive TDP43 pathology associated with cholesterol biosynthesis suppression

Canet-Pons, Júlia; Sen, Nesli-Ece; Arsovic, Aleksandar; Almaguer-Mederos, L.; Halbach, Melanie Vanessa; Key, Jana; Döring, Claudia; Kerksiek, Anja; Picchiarelli, Gina; Cassel, Raphaelle; Frydman, René; Dieterlé, Stéphane; Fuchs, Nina V.; König, Renate; Dupuis, Luc; Lütjohann, Dieter; Gispert, Suzana; Auburger, Georg

doi:10.1016/j.nbd.2021.105289

Cited by 27 publications

(23 citation statements)

References 249 publications

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“…The findings of several cholesterol derived oxysterols in the CSF and serum of ALS patients highlights a central role for altered oxysterol metabolism in ALS [28] and other motor neuron diseases, such as hereditary spastic paraplegia [37]. Interestingly, it seems that cholesterol biosynthesis is downregulated in several diseases related with motor dysfunction, as identified in an animal model of SCA2 and ALS, carrying an intermediate CAG expansion in the ATXN2 gene [38]. More studies on the role of cholesterol pathways in motor neuron diseases are needed.…”

Section: Discussionmentioning

confidence: 99%

A Transcriptomic Meta-Analysis Shows Lipid Metabolism Dysregulation as an Early Pathological Mechanism in the Spinal Cord of SOD1 Mice

Fernández-Beltrán

Godoy-Corchuelo

Losa-Fontangordo

et al. 2021

IJMS

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Amyotrophic lateral sclerosis (ALS) is a multifactorial and complex fatal degenerative disorder. A number of pathological mechanisms that lead to motor neuron death have been identified, although there are many unknowns in the disease aetiology of ALS. Alterations in lipid metabolism are well documented in the progression of ALS, both at the systemic level and in the spinal cord of mouse models and ALS patients. The origin of these lipid alterations remains unclear. This study aims to identify early lipid metabolic pathways altered before systemic metabolic symptoms in the spinal cord of mouse models of ALS. To do this, we performed a transcriptomic analysis of the spinal cord of SOD1G93A mice at an early disease stage, followed by a robust transcriptomic meta-analysis using publicly available RNA-seq data from the spinal cord of SOD1 mice at early and late symptomatic disease stages. The meta-analyses identified few lipid metabolic pathways dysregulated early that were exacerbated at symptomatic stages; mainly cholesterol biosynthesis, ceramide catabolism, and eicosanoid synthesis pathways. We present an insight into the pathological mechanisms in ALS, confirming that lipid metabolic alterations are transcriptionally dysregulated and are central to ALS aetiology, opening new options for the treatment of these devastating conditions.

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Section: Discussionmentioning

confidence: 99%

A Transcriptomic Meta-Analysis Shows Lipid Metabolism Dysregulation as an Early Pathological Mechanism in the Spinal Cord of SOD1 Mice

Fernández-Beltrán

Godoy-Corchuelo

Losa-Fontangordo

et al. 2021

IJMS

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“…Transgenic mice overexpressing HECW1 display neuronal loss in the spinal cord, muscular atrophy and microglia activation 64 , and the HECW1 protein has been shown to ubiquitinate mutant superoxide dismutase 1 (SOD1), typical of familial ALS patients 20 . Similar to Hecw, the expression of HECW1 seems to decline with aging 65 , suggesting the existence of a positive and protective role for this E3 ligase in the maintenance of neuronal homeostasis.…”

Section: Discussionmentioning

confidence: 98%

Hecw controls oogenesis and neuronal homeostasis by promoting the liquid state of ribonucleoprotein particles

et al. 2021

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Specialised ribonucleoprotein (RNP) granules are a hallmark of polarized cells, like neurons and germ cells. Among their main functions is the spatial and temporal modulation of the activity of specific mRNA transcripts that allow specification of primary embryonic axes. While RNPs composition and role are well established, their regulation is poorly defined. Here, we demonstrate that Hecw, a newly identified Drosophila ubiquitin ligase, is a key modulator of RNPs in oogenesis and neurons. Hecw depletion leads to the formation of enlarged granules that transition from a liquid to a gel-like state. Loss of Hecw activity results in defective oogenesis, premature aging and climbing defects associated with neuronal loss. At the molecular level, reduced ubiquitination of the Fmrp impairs its translational repressor activity, resulting in altered Orb expression in nurse cells and Profilin in neurons.

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“…In general, the SREBP2 pathway is robustly activated during sterol depletion. It has been reported that the level of HMG-CoA reductase is elevated in ALS spinal cord grey matter, that the SREBP2 expression level is declined in ALS model mice with mutant SOD1(36), and that Spinocerebellar Ataxia type 2 model mice harboring TDP-43 pathology exhibit concomitant cholesterol biogenesis suppression (37). Our observations suggest that TDP-43 inhibited the maintenance of the cellular cholesterol level by SREBP2, and that this impaired cholesterol metabolism, which is presumably involved in other neurodegenerative diseases including Alzheimer's disease (AD) and Huntington's disease (16,38,39), is crucial in the ALS pathophysiology.…”

Section: Discussionmentioning

confidence: 99%

ALS-Causing Protein TDP-43 Impairs SREBP2 Cholesterol Regulation

Egawa

Izumi

Tsuge

et al. 2021

Preprint

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Dyslipidemia is correlated with the prognosis of amyotrophic lateral sclerosis (ALS), a fatal motor neuron disorder characterized pathologically by TAR DNA binding protein (TDP-43) inclusions. We investigated molecular mechanisms of lipid metabolism regulated by TDP-43 in ALS. Expression microarray and RNA deep sequencing (RNA-Seq) were performed using cell lines expressing doxycycline-inductive TDP-43. Gene expression and transcriptome profiling identified 434 significantly altered genes under high levels of TDP-43 (Tukey’s test, P < 0.05) including sterol regulatory element-binding protein 2 (SREBP2), a master regulator of cholesterol homeostasis and its downstream genes. TDP-43 overexpression impaired SREBP2 transcriptional activity, leading to inhibition of cholesterol biosynthesis via the nutrient- and growth factor-responsive kinase mTOR Complex I (mTORC1). The amount of cholesterol was significantly decreased in motor neuronal cultures derived from ALS-patient induced pluripotent stem cells (iPSCs) as well as in the spinal fluids of ALS patients and in the spinal cord of ALS model mice. Impairment of cholesterol synthesis is caused by an increase in toxic function of TDP-43 in ALS.

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Atxn2-CAG100-KnockIn mouse spinal cord shows progressive TDP43 pathology associated with cholesterol biosynthesis suppression

Cited by 27 publications

References 249 publications

A Transcriptomic Meta-Analysis Shows Lipid Metabolism Dysregulation as an Early Pathological Mechanism in the Spinal Cord of SOD1 Mice

A Transcriptomic Meta-Analysis Shows Lipid Metabolism Dysregulation as an Early Pathological Mechanism in the Spinal Cord of SOD1 Mice

Hecw controls oogenesis and neuronal homeostasis by promoting the liquid state of ribonucleoprotein particles

ALS-Causing Protein TDP-43 Impairs SREBP2 Cholesterol Regulation

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