The cholesterol 24-hydroxylase activates autophagy and decreases mutant huntingtin build-up in a neuroblastoma culture model of Huntington’s disease

Nóbrega, Clévio; Conceição, André; Costa, Ricardo A.; Koppenol, Rebekah; Sequeira, Raquel L.; Nunes, Ricardo José; Carmo‐Silva, Sara; Marcelo, Adriana; Bétuing, Sandrine; Caboche, Jocelyne; Cartier, Nathalie; Alves, Sandro

doi:10.1186/s13104-020-05053-x

Cited by 13 publications

(9 citation statements)

References 50 publications

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“…72 Overexpression of cytochrome P450 family 46 subfamily a member 1 (CYP46A1), a cardinal enzyme in brain cholesterol metabolism, attenuated the size and quantity of mHTT aggregates in a neuroblastoma cell HD model which was linked to mild autophagy induction. 73 Huntingtin (HTT) plays various roles in mitophagy, selective autophagy of mitochondria, such as promoting mitophagy initiation and the recruitment of mitophagy receptors.…”

Section: Adap Tive Autophagy In Hdmentioning

confidence: 99%

Targeting autophagy in neurodegenerative diseases: From molecular mechanisms to clinical therapeutics

Ajoolabady

Aslkhodapasandhokmabad

Henninger

et al. 2021

Clin Exp Pharma Physio

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Macroautophagy (hereafter autophagy) is a eukaryotic intracellular process that includes long-lived and damaged organelles, aggregated and misfolded proteins, as well as superfluous cellular components by forming a transitory double-membrane structure; namely, the phagophore. The phagophore hen matures into a double-membrane autophagosome. Mature autophagosomes then fuse with lysosomes to degrade and recycle autophagy products into their building

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Section: Adap Tive Autophagy In Hdmentioning

confidence: 99%

Targeting autophagy in neurodegenerative diseases: From molecular mechanisms to clinical therapeutics

Ajoolabady

Aslkhodapasandhokmabad

Henninger

et al. 2021

Clin Exp Pharma Physio

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“…The 24OHC-liked compound reversed schizophrenia-liked behavioral in animal models provides strong evidence for this hypothesis ( 22 ). On the other hand, previous studies have been indicated that 24OHC may facilitate inflammation, oxidative stress, autophagy, and necroptosis, which are also main driving forces in schizophrenia ( 51 – 53 ). These data implied that lowering 24OHC levels might be a therapeutic way in schizophrenia treatment.…”

Section: Discussionmentioning

confidence: 93%

Brain-Specific Oxysterols and Risk of Schizophrenia in Clinical High-Risk Subjects and Patients With Schizophrenia

Sun

Zhao

et al. 2021

Front. Psychiatry

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Accumulating evidence from clinical, genetic, and epidemiologic studies suggest that schizophrenia might be a neuronal development disorder. While oxysterols are important factors in neurodevelopment, it is unknown whether oxysterols might be involved in development of schizophrenia. The present study investigated the relationship between tissue-specifically originated oxysterols and risk of schizophrenia. A total of 216 individuals were recruited in this study, including 76 schizophrenia patients, 39 clinical high-risk (CHR) subjects, and 101 healthy controls (HC). We investigated the circulating levels of brain-specific oxysterol 24(S)-hydroxycholesterol (24OHC) and peripheral oxysterol 27-hydroxycholesterol (27OHC) in all participants and analyzed the potential links between the oxysterols and specific clinical symptoms in schizophrenic patients and CHR. Our data showed an elevation of 24OHC in both schizophrenia patients and CHR than that in HC, while a lower level of 27OHC in the schizophrenia group only. The ratio of 24OHC to 27OHC was only increased in the schizophrenic group compared with CHR and HC. For the schizophrenic patients, the circulating 24OHC levels are significantly associated with disease duration, positively correlated with the positive and negative syndrome total scores, while the 27OHC levels were inversely correlated with the positive symptom scores. Together, our data demonstrated the disruption of tissue-specifically originated cholesterol metabolism in schizophrenia and CHR, suggesting the circulating 24OHC or 24OHC/27OHC ratio might not only be a potential indicator for risk for schizophrenia but also be biomarkers for functional abnormalities in neuropathology of schizophrenia.

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“…Other studies support the role of CYP46A1 overexpression in alleviating HD phenotypes. Indeed, in a neuroblastoma culture model of HD, CYP46A1 over-expression reduces the quantity and size of mHTT aggregates, as well as the levels of mHTT protein, potentially through the activation of autophagy ( Nóbrega et al, 2020 ). Interestingly, CYP46A1 overexpression protects against NMDA-mediated excitotoxicity in a cellular model of HD ( Boussicault et al, 2018 ).…”

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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The cholesterol 24-hydroxylase activates autophagy and decreases mutant huntingtin build-up in a neuroblastoma culture model of Huntington’s disease

Cited by 13 publications

References 50 publications

Targeting autophagy in neurodegenerative diseases: From molecular mechanisms to clinical therapeutics

Targeting autophagy in neurodegenerative diseases: From molecular mechanisms to clinical therapeutics

Brain-Specific Oxysterols and Risk of Schizophrenia in Clinical High-Risk Subjects and Patients With Schizophrenia

Altered Cholesterol Homeostasis in Huntington’s Disease

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