Glial Cell Dysfunction in <i>C9orf72</i>-Related Amyotrophic Lateral Sclerosis and Frontotemporal Dementia
Since the discovery of the chromosome 9 open reading frame 72 (<i>C9orf72</i>) repeat expansion mutation in 2011 as the most common genetic abnormality in amyotrophic lateral sclerosis (ALS, also known as Lou Gehrig’s disease) and frontotemporal dementia (FTD), progress in understanding...
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| Format: | Article |
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MDPI AG
2021-01-01
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| Series: | Cells |
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| Online Access: | https://www.mdpi.com/2073-4409/10/2/249 |
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| author | Mehdi Ghasemi Kiandokht Keyhanian Catherine Douthwright |
| author_facet | Mehdi Ghasemi Kiandokht Keyhanian Catherine Douthwright |
| author_sort | Mehdi Ghasemi |
| collection | DOAJ |
| description | Since the discovery of the chromosome 9 open reading frame 72 (<i>C9orf72</i>) repeat expansion mutation in 2011 as the most common genetic abnormality in amyotrophic lateral sclerosis (ALS, also known as Lou Gehrig’s disease) and frontotemporal dementia (FTD), progress in understanding the signaling pathways related to this mutation can only be described as intriguing. Two major theories have been suggested—(i) loss of function or haploinsufficiency and (ii) toxic gain of function from either <i>C9orf72</i> repeat RNA or dipeptide repeat proteins (DPRs) generated from repeat-associated non-ATG (RAN) translation. Each theory has provided various signaling pathways that potentially participate in the disease progression. Dysregulation of the immune system, particularly glial cell dysfunction (mainly microglia and astrocytes), is demonstrated to play a pivotal role in both loss and gain of function theories of <i>C9orf72</i> pathogenesis. In this review, we discuss the pathogenic roles of glial cells in <i>C9orf72</i> ALS/FTD as evidenced by pre-clinical and clinical studies showing the presence of gliosis in <i>C9orf72</i> ALS/FTD, pathologic hallmarks in glial cells, including TAR DNA-binding protein 43 (TDP-43) and p62 aggregates, and toxicity of <i>C9orf72</i> glial cells. A better understanding of these pathways can provide new insights into the development of therapies targeting glial cell abnormalities in <i>C9orf72</i> ALS/FTD. |
| first_indexed | 2024-03-09T03:28:32Z |
| format | Article |
| id | doaj.art-8a002479f86d4af393ef6712ef3e0c32 |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-09T03:28:32Z |
| publishDate | 2021-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-8a002479f86d4af393ef6712ef3e0c322023-12-03T14:59:32ZengMDPI AGCells2073-44092021-01-0110224910.3390/cells10020249Glial Cell Dysfunction in <i>C9orf72</i>-Related Amyotrophic Lateral Sclerosis and Frontotemporal DementiaMehdi Ghasemi0Kiandokht Keyhanian1Catherine Douthwright2Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01655, USADepartment of Neurology, University of Massachusetts Medical School, Worcester, MA 01655, USADepartment of Neurology, University of Massachusetts Medical School, Worcester, MA 01655, USASince the discovery of the chromosome 9 open reading frame 72 (<i>C9orf72</i>) repeat expansion mutation in 2011 as the most common genetic abnormality in amyotrophic lateral sclerosis (ALS, also known as Lou Gehrig’s disease) and frontotemporal dementia (FTD), progress in understanding the signaling pathways related to this mutation can only be described as intriguing. Two major theories have been suggested—(i) loss of function or haploinsufficiency and (ii) toxic gain of function from either <i>C9orf72</i> repeat RNA or dipeptide repeat proteins (DPRs) generated from repeat-associated non-ATG (RAN) translation. Each theory has provided various signaling pathways that potentially participate in the disease progression. Dysregulation of the immune system, particularly glial cell dysfunction (mainly microglia and astrocytes), is demonstrated to play a pivotal role in both loss and gain of function theories of <i>C9orf72</i> pathogenesis. In this review, we discuss the pathogenic roles of glial cells in <i>C9orf72</i> ALS/FTD as evidenced by pre-clinical and clinical studies showing the presence of gliosis in <i>C9orf72</i> ALS/FTD, pathologic hallmarks in glial cells, including TAR DNA-binding protein 43 (TDP-43) and p62 aggregates, and toxicity of <i>C9orf72</i> glial cells. A better understanding of these pathways can provide new insights into the development of therapies targeting glial cell abnormalities in <i>C9orf72</i> ALS/FTD.https://www.mdpi.com/2073-4409/10/2/249<i>C9orf72</i> gene<i>C9orf72</i> repeat expansion mutationamyotrophic lateral sclerosis (ALS)frontotemporal dementia (FTD)astrocytesmicroglia |
| spellingShingle | Mehdi Ghasemi Kiandokht Keyhanian Catherine Douthwright Glial Cell Dysfunction in <i>C9orf72</i>-Related Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Cells <i>C9orf72</i> gene <i>C9orf72</i> repeat expansion mutation amyotrophic lateral sclerosis (ALS) frontotemporal dementia (FTD) astrocytes microglia |
| title | Glial Cell Dysfunction in <i>C9orf72</i>-Related Amyotrophic Lateral Sclerosis and Frontotemporal Dementia |
| title_full | Glial Cell Dysfunction in <i>C9orf72</i>-Related Amyotrophic Lateral Sclerosis and Frontotemporal Dementia |
| title_fullStr | Glial Cell Dysfunction in <i>C9orf72</i>-Related Amyotrophic Lateral Sclerosis and Frontotemporal Dementia |
| title_full_unstemmed | Glial Cell Dysfunction in <i>C9orf72</i>-Related Amyotrophic Lateral Sclerosis and Frontotemporal Dementia |
| title_short | Glial Cell Dysfunction in <i>C9orf72</i>-Related Amyotrophic Lateral Sclerosis and Frontotemporal Dementia |
| title_sort | glial cell dysfunction in i c9orf72 i related amyotrophic lateral sclerosis and frontotemporal dementia |
| topic | <i>C9orf72</i> gene <i>C9orf72</i> repeat expansion mutation amyotrophic lateral sclerosis (ALS) frontotemporal dementia (FTD) astrocytes microglia |
| url | https://www.mdpi.com/2073-4409/10/2/249 |
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