C9orf72 gene networks in the human brain correlate with cortical thickness in C9-FTD and implicate vulnerable cell types
IntroductionA hexanucleotide repeat expansion (HRE) intronic to chromosome 9 open reading frame 72 (C9orf72) is recognized as the most common genetic cause of amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and ALS-FTD. Identifying genes that show similar regional co-expression p...
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Frontiers Media S.A.
2024-02-01
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| Series: | Frontiers in Neuroscience |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fnins.2024.1258996/full |
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| author | Iris J. Broce Iris J. Broce Daniel W. Sirkis Ryan M. Nillo Luke W. Bonham Luke W. Bonham Suzee E. Lee Bruce L. Miller Patricia A. Castruita Virginia E. Sturm Virginia E. Sturm Leo S. Sugrue Rahul S. Desikan Jennifer S. Yokoyama Jennifer S. Yokoyama Jennifer S. Yokoyama |
| author_facet | Iris J. Broce Iris J. Broce Daniel W. Sirkis Ryan M. Nillo Luke W. Bonham Luke W. Bonham Suzee E. Lee Bruce L. Miller Patricia A. Castruita Virginia E. Sturm Virginia E. Sturm Leo S. Sugrue Rahul S. Desikan Jennifer S. Yokoyama Jennifer S. Yokoyama Jennifer S. Yokoyama |
| author_sort | Iris J. Broce |
| collection | DOAJ |
| description | IntroductionA hexanucleotide repeat expansion (HRE) intronic to chromosome 9 open reading frame 72 (C9orf72) is recognized as the most common genetic cause of amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and ALS-FTD. Identifying genes that show similar regional co-expression patterns to C9orf72 may help identify novel gene targets and biological mechanisms that mediate selective vulnerability to ALS and FTD pathogenesis.MethodsWe leveraged mRNA expression data in healthy brain from the Allen Human Brain Atlas to evaluate C9orf72 co-expression patterns. To do this, we correlated average C9orf72 expression values in 51 regions across different anatomical divisions (cortex, subcortex, and cerebellum) with average gene expression values for 15,633 protein-coding genes, including 54 genes known to be associated with ALS, FTD, or ALS-FTD. We then performed imaging transcriptomic analyses to evaluate whether the identified C9orf72 co-expressed genes correlated with patterns of cortical thickness in symptomatic C9orf72 pathogenic HRE carriers (n = 19) compared to controls (n = 23). Lastly, we explored whether genes with significant C9orf72 imaging transcriptomic correlations (i.e., “C9orf72 imaging transcriptomic network”) were enriched in specific cell populations in the brain and enriched for specific biological and molecular pathways.ResultsA total of 2,120 genes showed an anatomical distribution of gene expression in the brain similar to C9orf72 and significantly correlated with patterns of cortical thickness in C9orf72 HRE carriers. This C9orf72 imaging transcriptomic network was differentially expressed in cell populations previously implicated in ALS and FTD, including layer 5b cells, cholinergic neurons in the spinal cord and brainstem and medium spiny neurons of the striatum, and was enriched for biological and molecular pathways associated with protein ubiquitination, autophagy, cellular response to DNA damage, endoplasmic reticulum to Golgi vesicle-mediated transport, among others.ConclusionConsidered together, we identified a network of C9orf72 associated genes that may influence selective regional and cell-type-specific vulnerabilities in ALS/FTD. |
| first_indexed | 2024-03-07T21:43:43Z |
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| language | English |
| last_indexed | 2024-03-07T21:43:43Z |
| publishDate | 2024-02-01 |
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| spelling | doaj.art-b13a9c462df547a2b3c345568ced924f2024-02-26T04:31:42ZengFrontiers Media S.A.Frontiers in Neuroscience1662-453X2024-02-011810.3389/fnins.2024.12589961258996C9orf72 gene networks in the human brain correlate with cortical thickness in C9-FTD and implicate vulnerable cell typesIris J. Broce0Iris J. Broce1Daniel W. Sirkis2Ryan M. Nillo3Luke W. Bonham4Luke W. Bonham5Suzee E. Lee6Bruce L. Miller7Patricia A. Castruita8Virginia E. Sturm9Virginia E. Sturm10Leo S. Sugrue11Rahul S. Desikan12Jennifer S. Yokoyama13Jennifer S. Yokoyama14Jennifer S. Yokoyama15Memory and Aging Center, Department of Neurology, Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, United StatesDepartment of Neurosciences, University of California San Diego, San Diego, CA, United StatesMemory and Aging Center, Department of Neurology, Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, United StatesDepartment of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, CA, United StatesMemory and Aging Center, Department of Neurology, Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, United StatesDepartment of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, CA, United StatesMemory and Aging Center, Department of Neurology, Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, United StatesMemory and Aging Center, Department of Neurology, Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, United StatesMemory and Aging Center, Department of Neurology, Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, United StatesMemory and Aging Center, Department of Neurology, Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, United StatesGlobal Brain Health Institute, University of California San Francisco, San Francisco, CA, United StatesDepartment of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, CA, United StatesDepartment of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, CA, United StatesMemory and Aging Center, Department of Neurology, Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, United StatesDepartment of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, CA, United StatesGlobal Brain Health Institute, University of California San Francisco, San Francisco, CA, United StatesIntroductionA hexanucleotide repeat expansion (HRE) intronic to chromosome 9 open reading frame 72 (C9orf72) is recognized as the most common genetic cause of amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and ALS-FTD. Identifying genes that show similar regional co-expression patterns to C9orf72 may help identify novel gene targets and biological mechanisms that mediate selective vulnerability to ALS and FTD pathogenesis.MethodsWe leveraged mRNA expression data in healthy brain from the Allen Human Brain Atlas to evaluate C9orf72 co-expression patterns. To do this, we correlated average C9orf72 expression values in 51 regions across different anatomical divisions (cortex, subcortex, and cerebellum) with average gene expression values for 15,633 protein-coding genes, including 54 genes known to be associated with ALS, FTD, or ALS-FTD. We then performed imaging transcriptomic analyses to evaluate whether the identified C9orf72 co-expressed genes correlated with patterns of cortical thickness in symptomatic C9orf72 pathogenic HRE carriers (n = 19) compared to controls (n = 23). Lastly, we explored whether genes with significant C9orf72 imaging transcriptomic correlations (i.e., “C9orf72 imaging transcriptomic network”) were enriched in specific cell populations in the brain and enriched for specific biological and molecular pathways.ResultsA total of 2,120 genes showed an anatomical distribution of gene expression in the brain similar to C9orf72 and significantly correlated with patterns of cortical thickness in C9orf72 HRE carriers. This C9orf72 imaging transcriptomic network was differentially expressed in cell populations previously implicated in ALS and FTD, including layer 5b cells, cholinergic neurons in the spinal cord and brainstem and medium spiny neurons of the striatum, and was enriched for biological and molecular pathways associated with protein ubiquitination, autophagy, cellular response to DNA damage, endoplasmic reticulum to Golgi vesicle-mediated transport, among others.ConclusionConsidered together, we identified a network of C9orf72 associated genes that may influence selective regional and cell-type-specific vulnerabilities in ALS/FTD.https://www.frontiersin.org/articles/10.3389/fnins.2024.1258996/fullC9orf72amyotrophic lateral sclerosisfrontotemporal dementiaimaging transcriptomicsgene networksneurodegeneration |
| spellingShingle | Iris J. Broce Iris J. Broce Daniel W. Sirkis Ryan M. Nillo Luke W. Bonham Luke W. Bonham Suzee E. Lee Bruce L. Miller Patricia A. Castruita Virginia E. Sturm Virginia E. Sturm Leo S. Sugrue Rahul S. Desikan Jennifer S. Yokoyama Jennifer S. Yokoyama Jennifer S. Yokoyama C9orf72 gene networks in the human brain correlate with cortical thickness in C9-FTD and implicate vulnerable cell types Frontiers in Neuroscience C9orf72 amyotrophic lateral sclerosis frontotemporal dementia imaging transcriptomics gene networks neurodegeneration |
| title | C9orf72 gene networks in the human brain correlate with cortical thickness in C9-FTD and implicate vulnerable cell types |
| title_full | C9orf72 gene networks in the human brain correlate with cortical thickness in C9-FTD and implicate vulnerable cell types |
| title_fullStr | C9orf72 gene networks in the human brain correlate with cortical thickness in C9-FTD and implicate vulnerable cell types |
| title_full_unstemmed | C9orf72 gene networks in the human brain correlate with cortical thickness in C9-FTD and implicate vulnerable cell types |
| title_short | C9orf72 gene networks in the human brain correlate with cortical thickness in C9-FTD and implicate vulnerable cell types |
| title_sort | c9orf72 gene networks in the human brain correlate with cortical thickness in c9 ftd and implicate vulnerable cell types |
| topic | C9orf72 amyotrophic lateral sclerosis frontotemporal dementia imaging transcriptomics gene networks neurodegeneration |
| url | https://www.frontiersin.org/articles/10.3389/fnins.2024.1258996/full |
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