Progranulin Deficiency Induces Mitochondrial Dysfunction in Frontotemporal Lobar Degeneration with TDP-43 Inclusions
Loss-of-function (LOF) mutations in <i>GRN</i> gene, which encodes progranulin (PGRN), cause frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP). FTLD-TDP is one of the most common forms of early onset dementia, but its pathogenesis is not fully understood. Mitochondrial...
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MDPI AG
2023-02-01
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| Series: | Antioxidants |
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| Online Access: | https://www.mdpi.com/2076-3921/12/3/581 |
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| author | Guiomar Rodríguez-Periñán Ana de la Encarnación Fermín Moreno Adolfo López de Munain Ana Martínez Ángeles Martín-Requero Carolina Alquézar Fernando Bartolomé |
| author_facet | Guiomar Rodríguez-Periñán Ana de la Encarnación Fermín Moreno Adolfo López de Munain Ana Martínez Ángeles Martín-Requero Carolina Alquézar Fernando Bartolomé |
| author_sort | Guiomar Rodríguez-Periñán |
| collection | DOAJ |
| description | Loss-of-function (LOF) mutations in <i>GRN</i> gene, which encodes progranulin (PGRN), cause frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP). FTLD-TDP is one of the most common forms of early onset dementia, but its pathogenesis is not fully understood. Mitochondrial dysfunction has been associated with several neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD) and amyotrophic lateral sclerosis (ALS). Here, we have investigated whether mitochondrial alterations could also contribute to the pathogenesis of PGRN deficiency-associated FTLD-TDP. Our results showed that PGRN deficiency induced mitochondrial depolarization, increased ROS production and lowered ATP levels in <i>GRN</i> KD SH-SY5Y neuroblastoma cells. Interestingly, lymphoblasts from FTLD-TDP patients carrying a LOF mutation in the <i>GRN</i> gene (c.709-1G > A) also demonstrated mitochondrial depolarization and lower ATP levels. Such mitochondrial damage increased mitochondrial fission to remove dysfunctional mitochondria by mitophagy. Interestingly, PGRN-deficient cells showed elevated mitochondrial mass together with autophagy dysfunction, implying that PGRN deficiency induced the accumulation of damaged mitochondria by blocking its degradation in the lysosomes. Importantly, the treatment with two brain-penetrant CK-1δ inhibitors (IGS-2.7 and IGS-3.27), known for preventing the phosphorylation and cytosolic accumulation of TDP-43, rescued mitochondrial function in PGRN-deficient cells. Taken together, these results suggest that mitochondrial function is impaired in FTLD-TDP associated with LOF <i>GRN</i> mutations and that the TDP-43 pathology linked to PGRN deficiency might be a key mechanism contributing to such mitochondrial dysfunction. Furthermore, our results point to the use of drugs targeting TDP-43 pathology as a promising therapeutic strategy for restoring mitochondrial function in FTLD-TDP and other TDP-43-related diseases. |
| first_indexed | 2024-03-11T07:00:38Z |
| format | Article |
| id | doaj.art-80545d043f2641519a191d78c80af40f |
| institution | Directory Open Access Journal |
| issn | 2076-3921 |
| language | English |
| last_indexed | 2024-03-11T07:00:38Z |
| publishDate | 2023-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Antioxidants |
| spelling | doaj.art-80545d043f2641519a191d78c80af40f2023-11-17T09:16:49ZengMDPI AGAntioxidants2076-39212023-02-0112358110.3390/antiox12030581Progranulin Deficiency Induces Mitochondrial Dysfunction in Frontotemporal Lobar Degeneration with TDP-43 InclusionsGuiomar Rodríguez-Periñán0Ana de la Encarnación1Fermín Moreno2Adolfo López de Munain3Ana Martínez4Ángeles Martín-Requero5Carolina Alquézar6Fernando Bartolomé7Group of Neurodegenerative Diseases, Hospital Universitario 12 de Octubre Research Institute (imas12), 28041 Madrid, SpainDepartment of Molecular Biomedicine, Centro de Investigaciones Biológicas, Margarita Salas (CSIC), Ramiro de Maeztu 9, 28040 Madrid, SpainNeuroscience Area, Biodonostia Health Research Institute, Donostia-San Sebastián, 20014 Gipuzkoa, SpainNeuroscience Area, Biodonostia Health Research Institute, Donostia-San Sebastián, 20014 Gipuzkoa, SpainCenter for Biomedical Research in Neurodegenerative Diseases (CIBERNED), Biomedical Research Networking Centers (CIBER), Institute Carlos III, 28031 Madrid, SpainDepartment of Molecular Biomedicine, Centro de Investigaciones Biológicas, Margarita Salas (CSIC), Ramiro de Maeztu 9, 28040 Madrid, SpainGroup of Neurodegenerative Diseases, Hospital Universitario 12 de Octubre Research Institute (imas12), 28041 Madrid, SpainGroup of Neurodegenerative Diseases, Hospital Universitario 12 de Octubre Research Institute (imas12), 28041 Madrid, SpainLoss-of-function (LOF) mutations in <i>GRN</i> gene, which encodes progranulin (PGRN), cause frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP). FTLD-TDP is one of the most common forms of early onset dementia, but its pathogenesis is not fully understood. Mitochondrial dysfunction has been associated with several neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD) and amyotrophic lateral sclerosis (ALS). Here, we have investigated whether mitochondrial alterations could also contribute to the pathogenesis of PGRN deficiency-associated FTLD-TDP. Our results showed that PGRN deficiency induced mitochondrial depolarization, increased ROS production and lowered ATP levels in <i>GRN</i> KD SH-SY5Y neuroblastoma cells. Interestingly, lymphoblasts from FTLD-TDP patients carrying a LOF mutation in the <i>GRN</i> gene (c.709-1G > A) also demonstrated mitochondrial depolarization and lower ATP levels. Such mitochondrial damage increased mitochondrial fission to remove dysfunctional mitochondria by mitophagy. Interestingly, PGRN-deficient cells showed elevated mitochondrial mass together with autophagy dysfunction, implying that PGRN deficiency induced the accumulation of damaged mitochondria by blocking its degradation in the lysosomes. Importantly, the treatment with two brain-penetrant CK-1δ inhibitors (IGS-2.7 and IGS-3.27), known for preventing the phosphorylation and cytosolic accumulation of TDP-43, rescued mitochondrial function in PGRN-deficient cells. Taken together, these results suggest that mitochondrial function is impaired in FTLD-TDP associated with LOF <i>GRN</i> mutations and that the TDP-43 pathology linked to PGRN deficiency might be a key mechanism contributing to such mitochondrial dysfunction. Furthermore, our results point to the use of drugs targeting TDP-43 pathology as a promising therapeutic strategy for restoring mitochondrial function in FTLD-TDP and other TDP-43-related diseases.https://www.mdpi.com/2076-3921/12/3/581progranulinFTLD-TDPmitochondriabioenergeticsmitophagyautophagy |
| spellingShingle | Guiomar Rodríguez-Periñán Ana de la Encarnación Fermín Moreno Adolfo López de Munain Ana Martínez Ángeles Martín-Requero Carolina Alquézar Fernando Bartolomé Progranulin Deficiency Induces Mitochondrial Dysfunction in Frontotemporal Lobar Degeneration with TDP-43 Inclusions Antioxidants progranulin FTLD-TDP mitochondria bioenergetics mitophagy autophagy |
| title | Progranulin Deficiency Induces Mitochondrial Dysfunction in Frontotemporal Lobar Degeneration with TDP-43 Inclusions |
| title_full | Progranulin Deficiency Induces Mitochondrial Dysfunction in Frontotemporal Lobar Degeneration with TDP-43 Inclusions |
| title_fullStr | Progranulin Deficiency Induces Mitochondrial Dysfunction in Frontotemporal Lobar Degeneration with TDP-43 Inclusions |
| title_full_unstemmed | Progranulin Deficiency Induces Mitochondrial Dysfunction in Frontotemporal Lobar Degeneration with TDP-43 Inclusions |
| title_short | Progranulin Deficiency Induces Mitochondrial Dysfunction in Frontotemporal Lobar Degeneration with TDP-43 Inclusions |
| title_sort | progranulin deficiency induces mitochondrial dysfunction in frontotemporal lobar degeneration with tdp 43 inclusions |
| topic | progranulin FTLD-TDP mitochondria bioenergetics mitophagy autophagy |
| url | https://www.mdpi.com/2076-3921/12/3/581 |
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