Non-Cell Autonomous and Epigenetic Mechanisms of Huntington's Disease.
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ABSTRACT:
SUBMITTER: Kim C
PROVIDER: S-EPMC8617801 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Huntington's disease is an autosomal dominant disorder caused by a mutation in the gene encoding the protein huntingtin on chromosome 4. The mutation is an expanded CAG repeat in the first exon, encoding a polyglutamine tract. If the polyglutamine tract is > 40, penetrance is 100% and death is inevitable. Despite the widespread expression of huntingtin, HD has long been considered primarily as a disease of the striatum. It is characterized by selective vulnerability with dysfunction followed by death of the medium size spiny neuron. Considerable effort is being expended to determine whether striatal damage is cell-autonomous, non-cell-autonomous, requiring cell-cell and region to region communication, or both. We review data supporting both mechanisms. We also attempt to organize the data into common mechanisms that may arise outside the medium, spiny neuron, but ultimately have their greatest impact in the striatum.
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Project description:Huntington's disease (HD) is an autosomal dominant disorder caused by an expansion in the trinucleotide CAG repeat in exon-1 in the huntingtin gene, located on chromosome 4. When the number of trinucleotide CAG exceeds 40 repeats, disease invariably is manifested, characterized by motor, cognitive, and psychiatric symptoms. The huntingtin (Htt) protein and its mutant form (mutant huntingtin, mHtt) are ubiquitously expressed but although multiple brain regions are affected, the most vulnerable brain region is the striatum. Striatal medium-sized spiny neurons (MSNs) preferentially degenerate, followed by the cortical pyramidal neurons located in layers V and VI. Proposed HD pathogenic mechanisms include, but are not restricted to, excitotoxicity, neurotrophic support deficits, collapse of the protein degradation mechanisms, mitochondrial dysfunction, transcriptional alterations, and disorders of myelin. Studies performed in cell type-specific and regionally selective HD mouse models implicate both MSN cell-autonomous properties and cell-cell interactions, particularly corticostriatal but also with non-neuronal cell types. Here, we review the intrinsic properties of MSNs that contribute to their selective vulnerability and in addition, we discuss how astrocytes, microglia, and oligodendrocytes, together with aberrant corticostriatal connectivity, contribute to HD pathophysiology. In addition, mHtt causes cell-autonomous dysfunction in cell types other than MSNs. These findings have implications in terms of therapeutic strategies aimed at preventing neuronal dysfunction and degeneration.
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Project description:Huntington's disease (HD) is an incurable and fatal hereditary neurodegenerative disorder of mid-life onset characterized by chorea, emotional distress, and progressive cognitive decline. HD is caused by an expansion of CAG repeats coding for glutamine (Q) in exon 1 of the huntingtin gene. Recent studies suggest that epigenetic modifications may play a key role in HD pathogenesis. Alterations of the epigenetic "histone code" lead to chromatin remodeling and deregulation of neuronal gene transcription that are prominently linked to HD pathogenesis. Furthermore, specific noncoding RNAs and microRNAs are associated with neuronal damage in HD. In this review, we discuss how DNA methylation, post-translational modifications of histone, and noncoding RNA function are affected and involved in HD pathogenesis. In addition, we summarize the therapeutic effects of histone deacetylase inhibitors and DNA binding drugs on epigenetic modifications and neuropathological sequelae in HD. Our understanding of the role of these epigenetic mechanisms may lead to the identification of novel biological markers and new therapeutic targets to treat HD.
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Project description:The Krox-20 gene encodes a zinc finger transcription factor, which has been shown previously, by targeted inactivation in the mouse, to be required for the development of rhombomeres (r) 3 and 5 in the segmented embryonic hindbrain. In the present work, Krox-20 was expressed ectopically in the developing chick hindbrain by use of electroporation. We demonstrate that Krox-20 expression is sufficient to confer odd-numbered rhombomere characteristics to r2, r4, and r6 cells, presumably in a cell-autonomous manner. Therefore, Krox-20, appears as the major determinant of odd-numbered identity within the hindbrain. In addition, we provide evidence for the existence of a non cell-autonomous autoactivation mechanism allowing recruitment of Krox-20-positive cells from even-numbered territories by neighboring Krox-20-expressing cells. On the basis of these observations, we propose that Krox-20 regulates multiple, intertwined steps in segmental patterning: Initial activation of Krox-20 in a few cells leads to the segregation, homogenization, and possibly expansion of territories to which Krox-20 in addition confers an odd-numbered identity.
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Project description:Huntington's disease (HD) is a neurodegenerative disorder caused by a dominantly inherited CAG repeat expansion in the huntingtin gene (HTT). Neuroinflammation and microglia have been implicated in HD pathology, however it has been unclear if mutant HTT (mHTT) expression has an adverse cell-autonomous effect on microglial function, or if they are only activated in response to the neurodegenerative brain environment in HD. To establish a human cell model of HD microglia function, we generated isogenic controls for HD patient-derived induced pluripotent stem cells (iPSC) with 109 CAG repeats (Q109). Q109 and isogenic Q22 iPSC, as well as non-isogenic Q60 and Q33 iPSC lines, were differentiated to iPSC-microglia. Our study supports a model of basal microglia dysfunction in HD leading to elevated pro-inflammatory cytokine production together with impaired phagocytosis and endocytosis capacity, in the absence of immune stimulation. These findings are consistent with early microglia activation observed in pre-manifest patients and indicate that mHTT gene expression affects microglia function in a cell-autonomous way.
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Project description:Studies of PrPC-derived prion disease generally focus on neurodegeneration. However, little is known regarding the modulation of hematopoietic stem progenitor cells (HSPCs) that express PrPC in prion infection. Among bone marrow (BM) hematopoietic cells, hematopoietic stem cells (HSCs) strongly express PrPC. A bioassay revealed the presence of misfolded prion protein (PrPSc) in BM cells derived from prion-infected mice; these BM cells demonstrated reproducible prion infectivity. At 5 months after infection with ME7, mice exhibited a significant decrease in the number of HSPCs. This decrease was mainly driven by increased apoptotic cell death, rather than cell cycle progression and senescence, in PrPC-positive but not PrPC-negative HSPC populations through a cell-autonomous mechanism. Notably, both PrPC-positive and PrPC-negative HSCs underwent cellular senescence, as indicated by high levels of senescence-associated factors and deficits in repopulation and self-renewal capacities at 7 months after infection. Senescence of HSCs occurred in the ME7-impaired BM microenvironment with aging phenotypes through non-cell autonomous mechanisms. These data provide novel evidence that prion infection differentially modulates HSC fate through both cell-autonomous and non-autonomous mechanisms.
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Project description:Huntington's disease (HD) is a devastating and fatal monogenic neurodegenerative disorder characterized by progressive loss of selective neurons in the brain and is caused by an abnormal expansion of CAG trinucleotide repeats in a coding exon of the huntingtin (HTT) gene. Progressive gene expression changes that begin at premanifest stages are a prominent feature of HD and are thought to contribute to disease progression. Increasing evidence suggests the critical involvement of epigenetic mechanisms in abnormal transcription in HD. Genome-wide alterations of a number of epigenetic modifications, including DNA methylation and multiple histone modifications, are associated with HD, suggesting that mutant HTT causes complex epigenetic abnormalities and chromatin structural changes, which may represent an underlying pathogenic mechanism. The causal relationship of specific epigenetic changes to early transcriptional alterations and to disease pathogenesis require further investigation. In this article, we review recent studies on epigenetic regulation in HD with a focus on DNA and histone modifications. We also discuss the contribution of epigenetic modifications to HD pathogenesis as well as potential mechanisms linking mutant HTT and epigenetic alterations. Finally, we discuss the therapeutic potential of epigenetic-based treatments.
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