P2X7 Receptor Upregulation in Huntington’s Disease Brains
Huntington’s disease (HD) is a fatal degenerative disorder affecting the nervous system. It is characterized by motor, cognitive, and psychiatric dysfunctions, with a late onset and an autosomal dominant pattern of inheritance. HD-causing mutation consists in an expansion of repeated CAG triplets in...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2020-10-01
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| Series: | Frontiers in Molecular Neuroscience |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fnmol.2020.567430/full |
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| author | Ivana Ollà Ivana Ollà María Santos-Galindo María Santos-Galindo Ainara Elorza Ainara Elorza José J. Lucas José J. Lucas |
| author_facet | Ivana Ollà Ivana Ollà María Santos-Galindo María Santos-Galindo Ainara Elorza Ainara Elorza José J. Lucas José J. Lucas |
| author_sort | Ivana Ollà |
| collection | DOAJ |
| description | Huntington’s disease (HD) is a fatal degenerative disorder affecting the nervous system. It is characterized by motor, cognitive, and psychiatric dysfunctions, with a late onset and an autosomal dominant pattern of inheritance. HD-causing mutation consists in an expansion of repeated CAG triplets in the huntingtin gene (HTT), encoding for an expanded polyglutamine (polyQ) stretch in the huntingtin protein (htt). The mutation causes neuronal dysfunction and loss through multiple mechanisms, affecting both the nucleus and cytoplasm. P2X7 receptor (P2X7R) emerged as a major player in neuroinflammation, since ATP – its endogenous ligand – is massively released under this condition. Indeed, P2X7R stimulation in the central nervous system (CNS) is known to enhance the release of pro-inflammatory cytokines from microglia and of neurotransmitters from neuronal presynaptic terminals, as well as to promote apoptosis. Previous experiments performed with neurons expressing the mutant huntingtin and exploiting HD mouse models demonstrated a role of P2X7R in HD. On the basis of those results, here, we explore for the first time the status of P2X7R in HD patients’ brain. We report that in HD postmortem striatum, as earlier observed in HD mice, the protein levels of the full-length form of P2X7R, also named P2X7R-A, are upregulated. In addition, the exclusively human naturally occurring variant lacking the C-terminus region, P2X7R-B, is upregulated as well. As we show here, this augmented protein levels can be explained by elevated mRNA levels. Furthermore, in HD patients’ striatum, P2X7R shows not only an augmented total transcript level but also an alteration of its splicing. Remarkably, P2X7R introns 10 and 11 are more retained in HD patients when compared with controls. Taken together, our data confirm that P2X7R is altered in brains of HD subjects and strengthen the notion that P2X7R may represent a potential therapeutic target for HD. |
| first_indexed | 2024-12-12T18:28:04Z |
| format | Article |
| id | doaj.art-687130fad692454987fcab0e8eefbfc9 |
| institution | Directory Open Access Journal |
| issn | 1662-5099 |
| language | English |
| last_indexed | 2024-12-12T18:28:04Z |
| publishDate | 2020-10-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Molecular Neuroscience |
| spelling | doaj.art-687130fad692454987fcab0e8eefbfc92022-12-22T00:15:59ZengFrontiers Media S.A.Frontiers in Molecular Neuroscience1662-50992020-10-011310.3389/fnmol.2020.567430567430P2X7 Receptor Upregulation in Huntington’s Disease BrainsIvana Ollà0Ivana Ollà1María Santos-Galindo2María Santos-Galindo3Ainara Elorza4Ainara Elorza5José J. Lucas6José J. Lucas7Centro de Biología Molecular ‘Severo Ochoa’ (CBMSO) CSIC/UAM, Madrid, SpainNetworking Research Centre on Neurodegenerative Diseases (CIBERNED), Madrid, SpainCentro de Biología Molecular ‘Severo Ochoa’ (CBMSO) CSIC/UAM, Madrid, SpainNetworking Research Centre on Neurodegenerative Diseases (CIBERNED), Madrid, SpainCentro de Biología Molecular ‘Severo Ochoa’ (CBMSO) CSIC/UAM, Madrid, SpainNetworking Research Centre on Neurodegenerative Diseases (CIBERNED), Madrid, SpainCentro de Biología Molecular ‘Severo Ochoa’ (CBMSO) CSIC/UAM, Madrid, SpainNetworking Research Centre on Neurodegenerative Diseases (CIBERNED), Madrid, SpainHuntington’s disease (HD) is a fatal degenerative disorder affecting the nervous system. It is characterized by motor, cognitive, and psychiatric dysfunctions, with a late onset and an autosomal dominant pattern of inheritance. HD-causing mutation consists in an expansion of repeated CAG triplets in the huntingtin gene (HTT), encoding for an expanded polyglutamine (polyQ) stretch in the huntingtin protein (htt). The mutation causes neuronal dysfunction and loss through multiple mechanisms, affecting both the nucleus and cytoplasm. P2X7 receptor (P2X7R) emerged as a major player in neuroinflammation, since ATP – its endogenous ligand – is massively released under this condition. Indeed, P2X7R stimulation in the central nervous system (CNS) is known to enhance the release of pro-inflammatory cytokines from microglia and of neurotransmitters from neuronal presynaptic terminals, as well as to promote apoptosis. Previous experiments performed with neurons expressing the mutant huntingtin and exploiting HD mouse models demonstrated a role of P2X7R in HD. On the basis of those results, here, we explore for the first time the status of P2X7R in HD patients’ brain. We report that in HD postmortem striatum, as earlier observed in HD mice, the protein levels of the full-length form of P2X7R, also named P2X7R-A, are upregulated. In addition, the exclusively human naturally occurring variant lacking the C-terminus region, P2X7R-B, is upregulated as well. As we show here, this augmented protein levels can be explained by elevated mRNA levels. Furthermore, in HD patients’ striatum, P2X7R shows not only an augmented total transcript level but also an alteration of its splicing. Remarkably, P2X7R introns 10 and 11 are more retained in HD patients when compared with controls. Taken together, our data confirm that P2X7R is altered in brains of HD subjects and strengthen the notion that P2X7R may represent a potential therapeutic target for HD.https://www.frontiersin.org/article/10.3389/fnmol.2020.567430/fullP2X7purinesATPHuntington’s diseaseneuroinflammationneurodegenerative disease |
| spellingShingle | Ivana Ollà Ivana Ollà María Santos-Galindo María Santos-Galindo Ainara Elorza Ainara Elorza José J. Lucas José J. Lucas P2X7 Receptor Upregulation in Huntington’s Disease Brains Frontiers in Molecular Neuroscience P2X7 purines ATP Huntington’s disease neuroinflammation neurodegenerative disease |
| title | P2X7 Receptor Upregulation in Huntington’s Disease Brains |
| title_full | P2X7 Receptor Upregulation in Huntington’s Disease Brains |
| title_fullStr | P2X7 Receptor Upregulation in Huntington’s Disease Brains |
| title_full_unstemmed | P2X7 Receptor Upregulation in Huntington’s Disease Brains |
| title_short | P2X7 Receptor Upregulation in Huntington’s Disease Brains |
| title_sort | p2x7 receptor upregulation in huntington s disease brains |
| topic | P2X7 purines ATP Huntington’s disease neuroinflammation neurodegenerative disease |
| url | https://www.frontiersin.org/article/10.3389/fnmol.2020.567430/full |
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