Cholesterol metabolism and homeostasis in the brain

Zhang, Juan; Liu, Qiang

doi:10.1007/s13238-014-0131-3

Cited by 473 publications

(322 citation statements)

References 130 publications

(124 reference statements)

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“…SREBF, sterol regulatory element binding factor. Color images available online at www.liebertpub .com/scd the major form of cholesterol in brain tissue [46]. We found that Dgcr8 -/-NSCs contain significantly lower levels of total and free cholesterol than Dgcr8 +/-NSCs (Fig.…”

Section: Fig 7 Dgcr8mentioning

confidence: 77%

Canonical microRNAs Enable Differentiation, Protect Against DNA Damage, and Promote Cholesterol Biosynthesis in Neural Stem Cells

Liu

Zhang

Khodadadi‐Jamayran

et al. 2017

Stem Cells and Development

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Neural stem cells (NSCs) have the capacity to differentiate into neurons, astrocytes, and oligodendrocytes, and therefore represent a promising donor tissue source for treating neurodegenerative diseases and repairing injuries of the nervous system. However, it remains unclear how canonical microRNAs (miRNAs), the subset of miRNAs requiring the Drosha-Dgcr8 microprocessor and the type III RNase Dicer for biogenesis, regulate NSCs. In this study, we established and characterized Dgcr8 -/-NSCs from conditionally Dgcr8-disrupted mouse embryonic brain. RNA-seq analysis demonstrated that disruption of Dgcr8 in NSCs causes a complete loss of canonical miRNAs and an accumulation of pri-miRNAs. Dgcr8-/-NSCs can be stably propagated in vitro, but progress through the cell cycle at reduced rates. When induced for differentiation, Dgcr8-/-NSCs failed to differentiate into neurons, astrocytes, or oligodendrocytes under permissive conditions. Compared to Dgcr8 +/-NSCs, Dgcr8 -/-NSCs exhibit significantly increased DNA damage. Comparative RNA-seq analysis and gene set enrichment analysis (GSEA) revealed that Dgcr8 -/-NSCs significantly downregulate genes associated with neuronal differentiation, cell cycle progression, DNA replication, protein translation, and DNA damage repair. Furthermore, we discovered that Dgcr8 -/-NSCs significantly downregulate genes responsible for cholesterol biosynthesis and demonstrated that Dgcr8 -/-NSCs contain lower levels of cholesterol. Together, our data demonstrate that canonical miRNAs play essential roles in enabling lineage specification, protecting DNA against damage, and promoting cholesterol biosynthesis in NSCs.

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Section: Fig 7 Dgcr8mentioning

confidence: 77%

Canonical microRNAs Enable Differentiation, Protect Against DNA Damage, and Promote Cholesterol Biosynthesis in Neural Stem Cells

Liu

Zhang

Khodadadi‐Jamayran

et al. 2017

Stem Cells and Development

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“…In fact, this treatment is particularly timely because cerebellar morphogenesis maximizes the need for cholesterol, making the exogenous LDL-uptaken cholesterol a rate-limiting factor for neurons [74, 75]. Noteworthy, CD administration didn’t rescue either GFAP hyper- or GLAST hypo-expression of Npc1 nmf164 mice, although it fully rescued Glutamine synthetase levels in these mice.…”

Section: Discussionmentioning

confidence: 99%

Developmental delay in motor skill acquisition in Niemann-Pick C1 mice reveals abnormal cerebellar morphogenesis

Caporali

Bruno

Palladino

et al. 2016

acta neuropathol commun

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Niemann-Pick type C1 (NPC1) disease is a lysosomal storage disorder caused by defective intracellular trafficking of exogenous cholesterol. Purkinje cell (PC) degeneration is the main sign of cerebellar dysfunction in both NPC1 patients and animal models. It has been recently shown that a significant decrease in Sonic hedgehog (Shh) expression reduces the proliferative potential of granule neuron precursors in the developing cerebellum of Npc1−/− mice. Pursuing the hypothesis that this developmental defect translates into functional impairments, we have assayed Npc1-deficient pups belonging to the milder mutant mouse strain Npc1nmf164 for sensorimotor development from postnatal day (PN) 3 to PN21. Npc1nmf164/ Npc1nmf164 pups displayed a 2.5-day delay in the acquisition of complex motor abilities compared to wild-type (wt) littermates, in agreement with the significant disorganization of cerebellar cortex cytoarchitecture observed between PN11 and PN15. Compared to wt, Npc1nmf164 homozygous mice exhibited a poorer morphological differentiation of Bergmann glia (BG), as indicated by thicker radial shafts and less elaborate reticular pattern of lateral processes. Also BG functional development was defective, as indicated by the significant reduction in GLAST and Glutamine synthetase expression. A reduced VGluT2 and GAD65 expression also indicated an overall derangement of the glutamatergic/GABAergic stimulation that PCs receive by climbing/parallel fibers and basket/stellate cells, respectively. Lastly, Npc1-deficiency also affected oligodendrocyte differentiation as indicated by the strong reduction of myelin basic protein. Two sequential 2-hydroxypropyl-β-cyclodextrin administrations at PN4 and PN7 counteract these defects, partially preventing functional impairment of BG and fully restoring the normal patterns of glutamatergic/GABAergic stimulation to PCs.These findings indicate that in Npc1nmf164 homozygous mice the derangement of synaptic connectivity and dysmyelination during cerebellar morphogenesis largely anticipate motor deficits that are typically observed during adulthood.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-016-0370-z) contains supplementary material, which is available to authorized users.

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“…Lipids and cholesterol derivatives are essential for the CNS, where they function as key components of myelin sheets, synapses, dendrites, and intercellular signaling molecules (104,105). Defects in cholesterol metabolism are clearly described in neurodegenerative diseases (106).…”

Section: Sdtfs That Regulate Cholesterol and Lipid Metabolismmentioning

confidence: 99%