Reduction of inflammation and mitochondrial degeneration in mutant SOD1 mice through inhibition of voltage-gated potassium channel Kv1.3
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with no effective therapy, causing progressive loss of motor neurons in the spinal cord, brainstem, and motor cortex. Regardless of its genetic or sporadic origin, there is currently no cure for ALS or therapy that can reverse...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2024-01-01
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| Series: | Frontiers in Molecular Neuroscience |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fnmol.2023.1333745/full |
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| author | Patrizia Ratano Germana Cocozza Cecilia Pinchera Ludovica Maria Busdraghi Iva Cantando Katiuscia Martinello Mariarosaria Scioli Maria Rosito Paola Bezzi Paola Bezzi Sergio Fucile Sergio Fucile Heike Wulff Cristina Limatola Cristina Limatola Giuseppina D’Alessandro Giuseppina D’Alessandro |
| author_facet | Patrizia Ratano Germana Cocozza Cecilia Pinchera Ludovica Maria Busdraghi Iva Cantando Katiuscia Martinello Mariarosaria Scioli Maria Rosito Paola Bezzi Paola Bezzi Sergio Fucile Sergio Fucile Heike Wulff Cristina Limatola Cristina Limatola Giuseppina D’Alessandro Giuseppina D’Alessandro |
| author_sort | Patrizia Ratano |
| collection | DOAJ |
| description | Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with no effective therapy, causing progressive loss of motor neurons in the spinal cord, brainstem, and motor cortex. Regardless of its genetic or sporadic origin, there is currently no cure for ALS or therapy that can reverse or control its progression. In the present study, taking advantage of a human superoxide dismutase-1 mutant (hSOD1-G93A) mouse that recapitulates key pathological features of human ALS, we investigated the possible role of voltage-gated potassium channel Kv1.3 in disease progression. We found that chronic administration of the brain-penetrant Kv1.3 inhibitor, PAP-1 (40 mg/Kg), in early symptomatic mice (i) improves motor deficits and prolongs survival of diseased mice (ii) reduces astrocyte reactivity, microglial Kv1.3 expression, and serum pro-inflammatory soluble factors (iii) improves structural mitochondrial deficits in motor neuron mitochondria (iv) restores mitochondrial respiratory dysfunction. Taken together, these findings underscore the potential significance of Kv1.3 activity as a contributing factor to the metabolic disturbances observed in ALS. Consequently, targeting Kv1.3 presents a promising avenue for modulating disease progression, shedding new light on potential therapeutic strategies for ALS. |
| first_indexed | 2024-03-08T13:50:22Z |
| format | Article |
| id | doaj.art-7b0c83b8d0b3491eaf2f6c242eacace9 |
| institution | Directory Open Access Journal |
| issn | 1662-5099 |
| language | English |
| last_indexed | 2024-03-08T13:50:22Z |
| publishDate | 2024-01-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Molecular Neuroscience |
| spelling | doaj.art-7b0c83b8d0b3491eaf2f6c242eacace92024-01-16T04:30:45ZengFrontiers Media S.A.Frontiers in Molecular Neuroscience1662-50992024-01-011610.3389/fnmol.2023.13337451333745Reduction of inflammation and mitochondrial degeneration in mutant SOD1 mice through inhibition of voltage-gated potassium channel Kv1.3Patrizia Ratano0Germana Cocozza1Cecilia Pinchera2Ludovica Maria Busdraghi3Iva Cantando4Katiuscia Martinello5Mariarosaria Scioli6Maria Rosito7Paola Bezzi8Paola Bezzi9Sergio Fucile10Sergio Fucile11Heike Wulff12Cristina Limatola13Cristina Limatola14Giuseppina D’Alessandro15Giuseppina D’Alessandro16IRCCS Neuromed, Pozzilli, ItalyDepartment of Physiology and Pharmacology, University of Rome Sapienza, Rome, ItalyIRCCS Neuromed, Pozzilli, ItalyDepartment of Physiology and Pharmacology, University of Rome Sapienza, Rome, ItalyDepartment of Fundamental Neurosciences, University of Lausanne, Lausanne, SwitzerlandIRCCS Neuromed, Pozzilli, ItalyIRCCS Neuromed, Pozzilli, ItalyDepartment of Physiology and Pharmacology, University of Rome Sapienza, Rome, ItalyDepartment of Physiology and Pharmacology, University of Rome Sapienza, Rome, ItalyDepartment of Fundamental Neurosciences, University of Lausanne, Lausanne, SwitzerlandIRCCS Neuromed, Pozzilli, ItalyDepartment of Physiology and Pharmacology, University of Rome Sapienza, Rome, ItalyDepartment of Pharmacology, University of California Davis, Health Sciences Drive, Davis, CA, United StatesIRCCS Neuromed, Pozzilli, ItalyDepartment of Physiology and Pharmacology, Laboratory Affiliated to Istituto Pasteur, Sapienza University, Rome, ItalyIRCCS Neuromed, Pozzilli, ItalyDepartment of Physiology and Pharmacology, University of Rome Sapienza, Rome, ItalyAmyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with no effective therapy, causing progressive loss of motor neurons in the spinal cord, brainstem, and motor cortex. Regardless of its genetic or sporadic origin, there is currently no cure for ALS or therapy that can reverse or control its progression. In the present study, taking advantage of a human superoxide dismutase-1 mutant (hSOD1-G93A) mouse that recapitulates key pathological features of human ALS, we investigated the possible role of voltage-gated potassium channel Kv1.3 in disease progression. We found that chronic administration of the brain-penetrant Kv1.3 inhibitor, PAP-1 (40 mg/Kg), in early symptomatic mice (i) improves motor deficits and prolongs survival of diseased mice (ii) reduces astrocyte reactivity, microglial Kv1.3 expression, and serum pro-inflammatory soluble factors (iii) improves structural mitochondrial deficits in motor neuron mitochondria (iv) restores mitochondrial respiratory dysfunction. Taken together, these findings underscore the potential significance of Kv1.3 activity as a contributing factor to the metabolic disturbances observed in ALS. Consequently, targeting Kv1.3 presents a promising avenue for modulating disease progression, shedding new light on potential therapeutic strategies for ALS.https://www.frontiersin.org/articles/10.3389/fnmol.2023.1333745/fullALSmutant SOD1Kv1.3 channelsmitochondriainflammation |
| spellingShingle | Patrizia Ratano Germana Cocozza Cecilia Pinchera Ludovica Maria Busdraghi Iva Cantando Katiuscia Martinello Mariarosaria Scioli Maria Rosito Paola Bezzi Paola Bezzi Sergio Fucile Sergio Fucile Heike Wulff Cristina Limatola Cristina Limatola Giuseppina D’Alessandro Giuseppina D’Alessandro Reduction of inflammation and mitochondrial degeneration in mutant SOD1 mice through inhibition of voltage-gated potassium channel Kv1.3 Frontiers in Molecular Neuroscience ALS mutant SOD1 Kv1.3 channels mitochondria inflammation |
| title | Reduction of inflammation and mitochondrial degeneration in mutant SOD1 mice through inhibition of voltage-gated potassium channel Kv1.3 |
| title_full | Reduction of inflammation and mitochondrial degeneration in mutant SOD1 mice through inhibition of voltage-gated potassium channel Kv1.3 |
| title_fullStr | Reduction of inflammation and mitochondrial degeneration in mutant SOD1 mice through inhibition of voltage-gated potassium channel Kv1.3 |
| title_full_unstemmed | Reduction of inflammation and mitochondrial degeneration in mutant SOD1 mice through inhibition of voltage-gated potassium channel Kv1.3 |
| title_short | Reduction of inflammation and mitochondrial degeneration in mutant SOD1 mice through inhibition of voltage-gated potassium channel Kv1.3 |
| title_sort | reduction of inflammation and mitochondrial degeneration in mutant sod1 mice through inhibition of voltage gated potassium channel kv1 3 |
| topic | ALS mutant SOD1 Kv1.3 channels mitochondria inflammation |
| url | https://www.frontiersin.org/articles/10.3389/fnmol.2023.1333745/full |
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