A C9orf72 ALS/FTD Ortholog Acts in Endolysosomal Degradation and Lysosomal Homeostasis
The most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is the expansion of a hexanucleotide repeat in a non-coding region of the gene C9orf72. We report that loss-of-function mutations in alfa-1, the Caenorhabditis elegans ortholog of C9orf72, cause a...
| Main Authors: | , |
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| Other Authors: | |
| Format: | Article |
| Language: | English |
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Elsevier BV
2020
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| Online Access: | https://hdl.handle.net/1721.1/126268 |
| _version_ | 1826211295497551872 |
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| author | Corrionero Saiz, Ana Horvitz, Howard Robert |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Corrionero Saiz, Ana Horvitz, Howard Robert |
| author_sort | Corrionero Saiz, Ana |
| collection | MIT |
| description | The most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is the expansion of a hexanucleotide repeat in a non-coding region of the gene C9orf72. We report that loss-of-function mutations in alfa-1, the Caenorhabditis elegans ortholog of C9orf72, cause a novel phenotypic defect: endocytosed yolk is abnormally released into the extra-embryonic space, resulting in refractile “blobs.” The alfa-1 blob phenotype is partially rescued by the expression of the human C9orf72 protein, demonstrating that C9orf72 and alfa-1 function similarly. We show that alfa-1 and R144.5, which we identified from a genetic screen for mutants with the blob phenotype and renamed smcr-8, act in the degradation of endolysosomal content and subsequent lysosome reformation. The alfa-1 abnormality in lysosomal reformation results in a general dysregulation in lysosomal homeostasis, leading to defective degradation of phagosomal and autophagosomal contents. We suggest that, like alfa-1, C9orf72 functions in the degradation of endocytosed material and in the maintenance of lysosomal homeostasis. This previously undescribed function of C9orf72 explains a variety of disparate observations concerning the effects of mutations in C9orf72 and its homologs, including the abnormal accumulation of lysosomes and defective fusion of lysosomes to phagosomes. We suggest that aspects of the pathogenic and clinical features of ALS/FTD caused by C9orf72 mutations, such as altered immune responses, aggregation of autophagy targets, and excessive neuronal excitation, result from a reduction in C9orf72 gene function and consequent abnormalities in lysosomal degradation. Corrionero and Horvitz show that the C. elegans gene alfa-1 functions in the degradation of endocytosed material and hence has effects on subsequent lysosomal reformation and lysosomal homeostasis maintenance. Human C9orf72 functions similarly. Aspects of ALS/FTD might result from decreased C9orf72 function and defective lysosomal degradation. |
| first_indexed | 2024-09-23T15:03:40Z |
| format | Article |
| id | mit-1721.1/126268 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T15:03:40Z |
| publishDate | 2020 |
| publisher | Elsevier BV |
| record_format | dspace |
| spelling | mit-1721.1/1262682022-09-29T12:24:02Z A C9orf72 ALS/FTD Ortholog Acts in Endolysosomal Degradation and Lysosomal Homeostasis Corrionero Saiz, Ana Horvitz, Howard Robert Massachusetts Institute of Technology. Department of Biology McGovern Institute for Brain Research at MIT The most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is the expansion of a hexanucleotide repeat in a non-coding region of the gene C9orf72. We report that loss-of-function mutations in alfa-1, the Caenorhabditis elegans ortholog of C9orf72, cause a novel phenotypic defect: endocytosed yolk is abnormally released into the extra-embryonic space, resulting in refractile “blobs.” The alfa-1 blob phenotype is partially rescued by the expression of the human C9orf72 protein, demonstrating that C9orf72 and alfa-1 function similarly. We show that alfa-1 and R144.5, which we identified from a genetic screen for mutants with the blob phenotype and renamed smcr-8, act in the degradation of endolysosomal content and subsequent lysosome reformation. The alfa-1 abnormality in lysosomal reformation results in a general dysregulation in lysosomal homeostasis, leading to defective degradation of phagosomal and autophagosomal contents. We suggest that, like alfa-1, C9orf72 functions in the degradation of endocytosed material and in the maintenance of lysosomal homeostasis. This previously undescribed function of C9orf72 explains a variety of disparate observations concerning the effects of mutations in C9orf72 and its homologs, including the abnormal accumulation of lysosomes and defective fusion of lysosomes to phagosomes. We suggest that aspects of the pathogenic and clinical features of ALS/FTD caused by C9orf72 mutations, such as altered immune responses, aggregation of autophagy targets, and excessive neuronal excitation, result from a reduction in C9orf72 gene function and consequent abnormalities in lysosomal degradation. Corrionero and Horvitz show that the C. elegans gene alfa-1 functions in the degradation of endocytosed material and hence has effects on subsequent lysosomal reformation and lysosomal homeostasis maintenance. Human C9orf72 functions similarly. Aspects of ALS/FTD might result from decreased C9orf72 function and defective lysosomal degradation. 2020-07-20T21:03:15Z 2020-07-20T21:03:15Z 2018-05 2018-02 2020-07-17T13:50:22Z Article http://purl.org/eprint/type/JournalArticle 0960-9822 https://hdl.handle.net/1721.1/126268 Corrionero, Anna and H. Robert Horvitz. "A C9orf72 ALS/FTD Ortholog Acts in Endolysosomal Degradation and Lysosomal Homeostasis." Current Biology 28, 10 (May 2018): P1522-1535.e5 © 2018 Elsevier Ltd en http://dx.doi.org/10.1016/j.cub.2018.03.063 Current Biology Creative Commons Attribution-NonCommercial-NoDerivs License http://creativecommons.org/licenses/by-nc-nd/4.0/ application/octet-stream application/octet-stream application/pdf application/pdf application/pdf application/pdf application/pdf application/pdf application/pdf Elsevier BV Anna Corrionero |
| spellingShingle | Corrionero Saiz, Ana Horvitz, Howard Robert A C9orf72 ALS/FTD Ortholog Acts in Endolysosomal Degradation and Lysosomal Homeostasis |
| title | A C9orf72 ALS/FTD Ortholog Acts in Endolysosomal Degradation and Lysosomal Homeostasis |
| title_full | A C9orf72 ALS/FTD Ortholog Acts in Endolysosomal Degradation and Lysosomal Homeostasis |
| title_fullStr | A C9orf72 ALS/FTD Ortholog Acts in Endolysosomal Degradation and Lysosomal Homeostasis |
| title_full_unstemmed | A C9orf72 ALS/FTD Ortholog Acts in Endolysosomal Degradation and Lysosomal Homeostasis |
| title_short | A C9orf72 ALS/FTD Ortholog Acts in Endolysosomal Degradation and Lysosomal Homeostasis |
| title_sort | c9orf72 als ftd ortholog acts in endolysosomal degradation and lysosomal homeostasis |
| url | https://hdl.handle.net/1721.1/126268 |
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