Non-Cell Autonomous and Epigenetic Mechanisms of Huntington’s Disease
Abstract
:1. Introduction
2. Non-Cell Autonomous Cell Death Pathway in HD
2.1. Alteration of Astrocyte Function
2.2. Alteration of Oligodendrocyte Function
3. The Role of Epigenetic Modifications and Noncoding RNAs in the Pathogenesis of HD
4. Roles of Wild Type HTT (wtHTT) Versus mHTT in Vesicle Trafficking
5. Mitochondria Dysfunction in HD
6. Therapeutic Approaches for Huntington’s Disease
7. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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HD Pathology | Specimen | Brain Region/Cell Type | Experimental Method | Reference |
---|---|---|---|---|
Less EAAT2 mRNA | Postmortem | Cingulate cortex | RNA sequencing | [78] |
Neostriatum | In situ hybridization | [79] | ||
Less EAAT2 protein | Postmortem | Striatum | Immunohistochemistry | [34] |
Striatum, cortex | Western blot | [80] | ||
Mouse; R6/2 | Striatum, cortex, hippocampus, midbrain | Quantitative proteomics | [81] | |
Less glutamate uptake | Postmortem | Prefrontal cortex | Glutamate uptake assay | [84] |
Cell; astrocyte | differentiated from Q77 monkey iPSC | Glutamate uptake assay | [82] | |
Mouse; Q175 | Single corticostriatal synapse | Imaging assay with glutamate sensor | [83] | |
Less Kir4.1 mRNA | Postmortem | cingulate cortex | RNA sequencing | [78] |
Less Kir4.1 protein Higher extracellular K+More excitable | Mouse; R6/2 | Striatal MSN and astrocyte | qPCR, IHC, Western blot, Virus microinjection, Electrophysiology | [86] |
Altered Ca2+ signal | Mouse; R6/2 | Striatal astrocyte | Virus microinjectionElectrophysiology | [87] |
More excitotoxicity | Cell; neuron and astrocyte | Co-culture of HD neurons and astrocytes from human iPSC | Cell count after glutamate exposure | [89] |
Co-culture of wild type neurons with mHTT infected glia from rat primary culture | [90] |
Target | Strategy | Mode of Action | Disease Model | Clinical Trial & NCTno. | References |
---|---|---|---|---|---|
mHTT gene | CRISPR/Cas9 | Excise mHTT DNA selectively | Cell iPS | [174] | |
Mouse BacHD | [175] | ||||
Mouse HD140Q | [176] | ||||
Mouse R6/2 | [177] | ||||
KRAB-ZFPs | Inhibition of translation or transcriptdegradation | Mouse R6/1,2 | [178,179] | ||
shRNA | Mouse R6/2 | [180] | |||
Mouse N171-82Q | [181,182] | ||||
siRNA | Mouse HTT injected | [183] | |||
Mouse Hdh-150Q | [184] | ||||
miRNA | Mouse HD140Q | Phase I/II [235], NCT04120493 | [185] | ||
Antisense nucleotide | Bind to HTT mRNA | Mouse BACHD | Phase II, NCT02519036 | [236,237] | |
Transcriptional dysregulation | Phenylbutyrate | Inactivate histone deacetylase | Mouse N171-82Q | Phase II, NCT00212316 | [202] |
Sodium butyrate | Mouse R6/2 | [203] | |||
HDACi 4b | Mouse N171–82Q | [204,205,206] | |||
HDACi LBH589 | Transgenic Rodent HD Models | [207] | |||
Tubastatin A | Cell primary neuron | [208] | |||
CKD-504 | Phase I, NCT03713892 | ||||
Mithramycin | Increase H3K9 | Mouse R6/2 | [209] | ||
mHTT aggregation | Cystamine | Suppress mHTT crosslinking | Mouse R6/2 | [238,239] | |
Congo red | Bind and inhibit polyglutamineoligomerization | Mouse R6/2 | [240] | ||
ChrysamineG, Direct fast yellow | [210] | ||||
Trehalose | [211] | ||||
mHTT fragmentation | Minocycline | Inhibit caspase | Mouse R6/2 | Phase III, NCT00277355 | [241] |
Z-VAD-FMK | Cell X57 | [216] | |||
mHTT lowering | Blood transfusion | Remove circulating mHTT | Mouse zQ175 | [217] | |
mHTT post-modification | Insulin, exendin-4 | Increase mHTT Phosphorylation | Cell SH-SY5Y | [242] | |
GM1 | Mouse YAC128 | [243] | |||
RCAN1-1L | Cell ST14A | [244] | |||
SGK | Cell primary neuron | [245] | |||
Transactivation | KD3010 | Increased PPARδ transactivation | Mouse pCAGGS-loxP-STOP-loxP | [246] | |
Mitochondrial dysfunction | Creatine | Inactivate mitochondrial permeability transition | Mouse R6/2 | Phase II, NCT00026988 | [218] |
Coenzyme Q10 | Enhance electron transport | Phase II, NCT00920699 | [219,220] | ||
PGC-1α | Upregulate mitochondrial gene | [222] | |||
Metabolism | rhIGF-1 | increase glucose uptake | Mouse YAC128 Mouse R6/2 | [223] | |
Autophagy | Niclosamide | Inhibit mTOR | Cell HEK293, N2a | [225] | |
MAP4343, 17βE2, Isoquercitrin | Regulate stress response | C.elegans HD mutants | [228] | ||
Apoptosis | Z-VAD-FMK, Z-DEVD-FMK, Z-LEHD-FMK | Inhibit caspase | Cell primary neuron | [227] | |
PG3d | Cell COS-7 | [229] | |||
Lithium chloride | Rat QA injected | [230] | |||
Excitotoxicity | Memantine | Inhibit NMDA receptor | Phase IV, NCT00652457; Phase II, NCT00652457 | ||
Necrostatin-1 | Inhibit RIP1 kinase | Mouse R6/2 | [233,247] |
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Kim, C.; Yousefian-Jazi, A.; Choi, S.-H.; Chang, I.; Lee, J.; Ryu, H. Non-Cell Autonomous and Epigenetic Mechanisms of Huntington’s Disease. Int. J. Mol. Sci. 2021, 22, 12499. https://doi.org/10.3390/ijms222212499
Kim C, Yousefian-Jazi A, Choi S-H, Chang I, Lee J, Ryu H. Non-Cell Autonomous and Epigenetic Mechanisms of Huntington’s Disease. International Journal of Molecular Sciences. 2021; 22(22):12499. https://doi.org/10.3390/ijms222212499
Chicago/Turabian StyleKim, Chaebin, Ali Yousefian-Jazi, Seung-Hye Choi, Inyoung Chang, Junghee Lee, and Hoon Ryu. 2021. "Non-Cell Autonomous and Epigenetic Mechanisms of Huntington’s Disease" International Journal of Molecular Sciences 22, no. 22: 12499. https://doi.org/10.3390/ijms222212499