Sacsin Deletion Induces Aggregation of Glial Intermediate Filaments
Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a neurodegenerative disorder commonly diagnosed in infants and characterized by progressive cerebellar ataxia, spasticity, motor sensory neuropathy and axonal demyelination. ARSACS is caused by mutations in the SACS gene that lead...
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MDPI AG
2022-01-01
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| author | Fernanda Murtinheira Mafalda Migueis Ricardo Letra-Vilela Mickael Diallo Andrea Quezada Cláudia A. Valente Abel Oliva Carmen Rodriguez Vanesa Martin Federico Herrera |
| author_facet | Fernanda Murtinheira Mafalda Migueis Ricardo Letra-Vilela Mickael Diallo Andrea Quezada Cláudia A. Valente Abel Oliva Carmen Rodriguez Vanesa Martin Federico Herrera |
| author_sort | Fernanda Murtinheira |
| collection | DOAJ |
| description | Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a neurodegenerative disorder commonly diagnosed in infants and characterized by progressive cerebellar ataxia, spasticity, motor sensory neuropathy and axonal demyelination. ARSACS is caused by mutations in the SACS gene that lead to truncated or defective forms of the 520 kDa multidomain protein, sacsin. Sacsin function is exclusively studied on neuronal cells, where it regulates mitochondrial network organization and facilitates the normal polymerization of neuronal intermediate filaments (i.e., neurofilaments and vimentin). Here, we show that sacsin is also highly expressed in astrocytes, C6 rat glioma cells and N9 mouse microglia. Sacsin knockout in C6 cells (C6<sup>Sacs−/−</sup>) induced the accumulation of the glial intermediate filaments glial fibrillary acidic protein (GFAP), nestin and vimentin in the juxtanuclear area, and a concomitant depletion of mitochondria. C6<sup>Sacs−/−</sup> cells showed impaired responses to oxidative challenges (Rotenone) and inflammatory stimuli (Interleukin-6). GFAP aggregation is also associated with other neurodegenerative conditions diagnosed in infants, such as Alexander disease or Giant Axonal Neuropathy. Our results, and the similarities between these disorders, reinforce the possible connection between ARSACS and intermediate filament-associated diseases and point to a potential role of glia in ARSACS pathology. |
| first_indexed | 2024-03-10T01:43:20Z |
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| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-10T01:43:20Z |
| publishDate | 2022-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-6fd608b093224589afbfc1a1550049a42023-11-23T13:19:21ZengMDPI AGCells2073-44092022-01-0111229910.3390/cells11020299Sacsin Deletion Induces Aggregation of Glial Intermediate FilamentsFernanda Murtinheira0Mafalda Migueis1Ricardo Letra-Vilela2Mickael Diallo3Andrea Quezada4Cláudia A. Valente5Abel Oliva6Carmen Rodriguez7Vanesa Martin8Federico Herrera9Biosystems & Integrative Sciences Institute, Faculdade de Ciências, Universidade de Lisboa, 1649-004 Lisbon, PortugalBiosystems & Integrative Sciences Institute, Faculdade de Ciências, Universidade de Lisboa, 1649-004 Lisbon, PortugalBiosystems & Integrative Sciences Institute, Faculdade de Ciências, Universidade de Lisboa, 1649-004 Lisbon, PortugalBiosystems & Integrative Sciences Institute, Faculdade de Ciências, Universidade de Lisboa, 1649-004 Lisbon, PortugalBiosystems & Integrative Sciences Institute, Faculdade de Ciências, Universidade de Lisboa, 1649-004 Lisbon, PortugalInstituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisboa, PortugalInstituto de Tecnologia Quimica e Biologica (ITQB-NOVA), Universidade Nova de Lisboa, 2780-157 Oeiras, PortugalInstituto Universitario de Oncología del Principado de Asturias (IUOPA), Facultad de Medicina, Universidad de Oviedo, 33006 Oviedo, SpainInstituto Universitario de Oncología del Principado de Asturias (IUOPA), Facultad de Medicina, Universidad de Oviedo, 33006 Oviedo, SpainBiosystems & Integrative Sciences Institute, Faculdade de Ciências, Universidade de Lisboa, 1649-004 Lisbon, PortugalAutosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a neurodegenerative disorder commonly diagnosed in infants and characterized by progressive cerebellar ataxia, spasticity, motor sensory neuropathy and axonal demyelination. ARSACS is caused by mutations in the SACS gene that lead to truncated or defective forms of the 520 kDa multidomain protein, sacsin. Sacsin function is exclusively studied on neuronal cells, where it regulates mitochondrial network organization and facilitates the normal polymerization of neuronal intermediate filaments (i.e., neurofilaments and vimentin). Here, we show that sacsin is also highly expressed in astrocytes, C6 rat glioma cells and N9 mouse microglia. Sacsin knockout in C6 cells (C6<sup>Sacs−/−</sup>) induced the accumulation of the glial intermediate filaments glial fibrillary acidic protein (GFAP), nestin and vimentin in the juxtanuclear area, and a concomitant depletion of mitochondria. C6<sup>Sacs−/−</sup> cells showed impaired responses to oxidative challenges (Rotenone) and inflammatory stimuli (Interleukin-6). GFAP aggregation is also associated with other neurodegenerative conditions diagnosed in infants, such as Alexander disease or Giant Axonal Neuropathy. Our results, and the similarities between these disorders, reinforce the possible connection between ARSACS and intermediate filament-associated diseases and point to a potential role of glia in ARSACS pathology.https://www.mdpi.com/2073-4409/11/2/299ARSACSGFAPnestinvimentingliomaSTAT3 |
| spellingShingle | Fernanda Murtinheira Mafalda Migueis Ricardo Letra-Vilela Mickael Diallo Andrea Quezada Cláudia A. Valente Abel Oliva Carmen Rodriguez Vanesa Martin Federico Herrera Sacsin Deletion Induces Aggregation of Glial Intermediate Filaments Cells ARSACS GFAP nestin vimentin glioma STAT3 |
| title | Sacsin Deletion Induces Aggregation of Glial Intermediate Filaments |
| title_full | Sacsin Deletion Induces Aggregation of Glial Intermediate Filaments |
| title_fullStr | Sacsin Deletion Induces Aggregation of Glial Intermediate Filaments |
| title_full_unstemmed | Sacsin Deletion Induces Aggregation of Glial Intermediate Filaments |
| title_short | Sacsin Deletion Induces Aggregation of Glial Intermediate Filaments |
| title_sort | sacsin deletion induces aggregation of glial intermediate filaments |
| topic | ARSACS GFAP nestin vimentin glioma STAT3 |
| url | https://www.mdpi.com/2073-4409/11/2/299 |
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