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Glial dysregulation in the human brain in fragile X-associated tremor/ataxia syndrome
Short trinucleotide expansions at the FMR1 locus are associated with the late-onset condition fragile X-associated tremor/ataxia syndrome (FXTAS), which shows very different clinical and pathological features from fragile X syndrome (associated with longer expansions), with no clear molecular explan...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
National Academy of Sciences
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10265985/ https://www.ncbi.nlm.nih.gov/pubmed/37252957 http://dx.doi.org/10.1073/pnas.2300052120 |
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author | Dias, Caroline M. Issac, Biju Sun, Liang Lukowicz, Abigail Talukdar, Maya Akula, Shyam K. Miller, Michael B. Walsh, Katherine Rockowitz, Shira Walsh, Christopher A. |
author_facet | Dias, Caroline M. Issac, Biju Sun, Liang Lukowicz, Abigail Talukdar, Maya Akula, Shyam K. Miller, Michael B. Walsh, Katherine Rockowitz, Shira Walsh, Christopher A. |
author_sort | Dias, Caroline M. |
collection | PubMed |
description | Short trinucleotide expansions at the FMR1 locus are associated with the late-onset condition fragile X-associated tremor/ataxia syndrome (FXTAS), which shows very different clinical and pathological features from fragile X syndrome (associated with longer expansions), with no clear molecular explanation for these marked differences. One prevailing theory posits that the shorter, premutation expansion uniquely causes extreme neurotoxic increases in FMR1 mRNA (i.e., four to eightfold increases), but evidence to support this hypothesis is largely derived from analysis of peripheral blood. We applied single-nucleus RNA sequencing to postmortem frontal cortex and cerebellum from 7 individuals with premutation and matched controls (n = 6) to assess cell type–specific molecular neuropathology. We found only modest upregulation (~1.3-fold) of FMR1 in some glial populations associated with premutation expansions. In premutation cases, we also identified decreased astrocyte proportions in the cortex. Differential expression and gene ontology analysis demonstrated altered neuroregulatory roles of glia. Using network analyses, we identified cell type–specific and region-specific patterns of FMR1 protein target gene dysregulation unique to premutation cases, with notable network dysregulation in the cortical oligodendrocyte lineage. We used pseudotime trajectory analysis to determine how oligodendrocyte development was altered and identified differences in early gene expression in oligodendrocyte trajectories in premutation cases specifically, implicating early cortical glial developmental perturbations. These findings challenge dogma regarding extremely elevated FMR1 increases in FXTAS and implicate glial dysregulation as a critical facet of premutation pathophysiology, representing potential unique therapeutic targets directly derived from the human condition. |
format | Online Article Text |
id | pubmed-10265985 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | National Academy of Sciences |
record_format | MEDLINE/PubMed |
spelling | pubmed-102659852023-06-15 Glial dysregulation in the human brain in fragile X-associated tremor/ataxia syndrome Dias, Caroline M. Issac, Biju Sun, Liang Lukowicz, Abigail Talukdar, Maya Akula, Shyam K. Miller, Michael B. Walsh, Katherine Rockowitz, Shira Walsh, Christopher A. Proc Natl Acad Sci U S A Biological Sciences Short trinucleotide expansions at the FMR1 locus are associated with the late-onset condition fragile X-associated tremor/ataxia syndrome (FXTAS), which shows very different clinical and pathological features from fragile X syndrome (associated with longer expansions), with no clear molecular explanation for these marked differences. One prevailing theory posits that the shorter, premutation expansion uniquely causes extreme neurotoxic increases in FMR1 mRNA (i.e., four to eightfold increases), but evidence to support this hypothesis is largely derived from analysis of peripheral blood. We applied single-nucleus RNA sequencing to postmortem frontal cortex and cerebellum from 7 individuals with premutation and matched controls (n = 6) to assess cell type–specific molecular neuropathology. We found only modest upregulation (~1.3-fold) of FMR1 in some glial populations associated with premutation expansions. In premutation cases, we also identified decreased astrocyte proportions in the cortex. Differential expression and gene ontology analysis demonstrated altered neuroregulatory roles of glia. Using network analyses, we identified cell type–specific and region-specific patterns of FMR1 protein target gene dysregulation unique to premutation cases, with notable network dysregulation in the cortical oligodendrocyte lineage. We used pseudotime trajectory analysis to determine how oligodendrocyte development was altered and identified differences in early gene expression in oligodendrocyte trajectories in premutation cases specifically, implicating early cortical glial developmental perturbations. These findings challenge dogma regarding extremely elevated FMR1 increases in FXTAS and implicate glial dysregulation as a critical facet of premutation pathophysiology, representing potential unique therapeutic targets directly derived from the human condition. National Academy of Sciences 2023-05-30 2023-06-06 /pmc/articles/PMC10265985/ /pubmed/37252957 http://dx.doi.org/10.1073/pnas.2300052120 Text en Copyright © 2023 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by/4.0/This open access article is distributed under Creative Commons Attribution License 4.0 (CC BY) (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Biological Sciences Dias, Caroline M. Issac, Biju Sun, Liang Lukowicz, Abigail Talukdar, Maya Akula, Shyam K. Miller, Michael B. Walsh, Katherine Rockowitz, Shira Walsh, Christopher A. Glial dysregulation in the human brain in fragile X-associated tremor/ataxia syndrome |
title | Glial dysregulation in the human brain in fragile X-associated tremor/ataxia syndrome |
title_full | Glial dysregulation in the human brain in fragile X-associated tremor/ataxia syndrome |
title_fullStr | Glial dysregulation in the human brain in fragile X-associated tremor/ataxia syndrome |
title_full_unstemmed | Glial dysregulation in the human brain in fragile X-associated tremor/ataxia syndrome |
title_short | Glial dysregulation in the human brain in fragile X-associated tremor/ataxia syndrome |
title_sort | glial dysregulation in the human brain in fragile x-associated tremor/ataxia syndrome |
topic | Biological Sciences |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10265985/ https://www.ncbi.nlm.nih.gov/pubmed/37252957 http://dx.doi.org/10.1073/pnas.2300052120 |
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