Abnormal mitochondrial transport and morphology as early pathological changes in human models of spinal muscular atrophy
Spinal muscular atrophy (SMA), characterized by specific degeneration of spinal motor neurons, is caused by mutations in the survival of motor neuron 1, telomeric (SMN1) gene and subsequent decreased levels of functional SMN. How the deficiency of SMN, a ubiquitously expressed protein, leads to spin...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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The Company of Biologists
2016-01-01
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| Series: | Disease Models & Mechanisms |
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| Online Access: | http://dmm.biologists.org/content/9/1/39 |
| _version_ | 1818368421704761344 |
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| author | Chong-Chong Xu Kyle R. Denton Zhi-Bo Wang Xiaoqing Zhang Xue-Jun Li |
| author_facet | Chong-Chong Xu Kyle R. Denton Zhi-Bo Wang Xiaoqing Zhang Xue-Jun Li |
| author_sort | Chong-Chong Xu |
| collection | DOAJ |
| description | Spinal muscular atrophy (SMA), characterized by specific degeneration of spinal motor neurons, is caused by mutations in the survival of motor neuron 1, telomeric (SMN1) gene and subsequent decreased levels of functional SMN. How the deficiency of SMN, a ubiquitously expressed protein, leads to spinal motor neuron-specific degeneration in individuals affected by SMA remains unknown. In this study, we examined the role of SMN in mitochondrial axonal transport and morphology in human motor neurons by generating SMA type 1 patient-specific induced pluripotent stem cells (iPSCs) and differentiating these cells into spinal motor neurons. The initial specification of spinal motor neurons was not affected, but these SMA spinal motor neurons specifically degenerated following long-term culture. Moreover, at an early stage in SMA spinal motor neurons, but not in SMA forebrain neurons, the number of mitochondria, mitochondrial area and mitochondrial transport were significantly reduced in axons. Knocking down of SMN expression led to similar mitochondrial defects in spinal motor neurons derived from human embryonic stem cells, confirming that SMN deficiency results in impaired mitochondrial dynamics. Finally, the application of N-acetylcysteine (NAC) mitigated the impairment in mitochondrial transport and morphology and rescued motor neuron degeneration in SMA long-term cultures. Furthermore, NAC ameliorated the reduction in mitochondrial membrane potential in SMA spinal motor neurons, suggesting that NAC might rescue apoptosis and motor neuron degeneration by improving mitochondrial health. Overall, our data demonstrate that SMN deficiency results in abnormal mitochondrial transport and morphology and a subsequent reduction in mitochondrial health, which are implicated in the specific degeneration of spinal motor neurons in SMA. |
| first_indexed | 2024-12-13T23:07:41Z |
| format | Article |
| id | doaj.art-0abfd2d1f5d04bbd80886802d514dac5 |
| institution | Directory Open Access Journal |
| issn | 1754-8411 1754-8403 |
| language | English |
| last_indexed | 2024-12-13T23:07:41Z |
| publishDate | 2016-01-01 |
| publisher | The Company of Biologists |
| record_format | Article |
| series | Disease Models & Mechanisms |
| spelling | doaj.art-0abfd2d1f5d04bbd80886802d514dac52022-12-21T23:28:14ZengThe Company of BiologistsDisease Models & Mechanisms1754-84111754-84032016-01-0191394910.1242/dmm.021766021766Abnormal mitochondrial transport and morphology as early pathological changes in human models of spinal muscular atrophyChong-Chong Xu0Kyle R. Denton1Zhi-Bo Wang2Xiaoqing Zhang3Xue-Jun Li4 Department of Neuroscience, University of Connecticut Health Center, Farmington, CT 06030, USA Department of Neuroscience, University of Connecticut Health Center, Farmington, CT 06030, USA Department of Neuroscience, University of Connecticut Health Center, Farmington, CT 06030, USA Department of Regenerative Medicine, Tongji University School of Medicine, Shanghai 200092, China Department of Neuroscience, University of Connecticut Health Center, Farmington, CT 06030, USA Spinal muscular atrophy (SMA), characterized by specific degeneration of spinal motor neurons, is caused by mutations in the survival of motor neuron 1, telomeric (SMN1) gene and subsequent decreased levels of functional SMN. How the deficiency of SMN, a ubiquitously expressed protein, leads to spinal motor neuron-specific degeneration in individuals affected by SMA remains unknown. In this study, we examined the role of SMN in mitochondrial axonal transport and morphology in human motor neurons by generating SMA type 1 patient-specific induced pluripotent stem cells (iPSCs) and differentiating these cells into spinal motor neurons. The initial specification of spinal motor neurons was not affected, but these SMA spinal motor neurons specifically degenerated following long-term culture. Moreover, at an early stage in SMA spinal motor neurons, but not in SMA forebrain neurons, the number of mitochondria, mitochondrial area and mitochondrial transport were significantly reduced in axons. Knocking down of SMN expression led to similar mitochondrial defects in spinal motor neurons derived from human embryonic stem cells, confirming that SMN deficiency results in impaired mitochondrial dynamics. Finally, the application of N-acetylcysteine (NAC) mitigated the impairment in mitochondrial transport and morphology and rescued motor neuron degeneration in SMA long-term cultures. Furthermore, NAC ameliorated the reduction in mitochondrial membrane potential in SMA spinal motor neurons, suggesting that NAC might rescue apoptosis and motor neuron degeneration by improving mitochondrial health. Overall, our data demonstrate that SMN deficiency results in abnormal mitochondrial transport and morphology and a subsequent reduction in mitochondrial health, which are implicated in the specific degeneration of spinal motor neurons in SMA.http://dmm.biologists.org/content/9/1/39Induced pluripotent stem cellsiPSCsHuman embryonic stem cellshESCsSpinal muscular atrophyMitochondrial transport and morphology |
| spellingShingle | Chong-Chong Xu Kyle R. Denton Zhi-Bo Wang Xiaoqing Zhang Xue-Jun Li Abnormal mitochondrial transport and morphology as early pathological changes in human models of spinal muscular atrophy Disease Models & Mechanisms Induced pluripotent stem cells iPSCs Human embryonic stem cells hESCs Spinal muscular atrophy Mitochondrial transport and morphology |
| title | Abnormal mitochondrial transport and morphology as early pathological changes in human models of spinal muscular atrophy |
| title_full | Abnormal mitochondrial transport and morphology as early pathological changes in human models of spinal muscular atrophy |
| title_fullStr | Abnormal mitochondrial transport and morphology as early pathological changes in human models of spinal muscular atrophy |
| title_full_unstemmed | Abnormal mitochondrial transport and morphology as early pathological changes in human models of spinal muscular atrophy |
| title_short | Abnormal mitochondrial transport and morphology as early pathological changes in human models of spinal muscular atrophy |
| title_sort | abnormal mitochondrial transport and morphology as early pathological changes in human models of spinal muscular atrophy |
| topic | Induced pluripotent stem cells iPSCs Human embryonic stem cells hESCs Spinal muscular atrophy Mitochondrial transport and morphology |
| url | http://dmm.biologists.org/content/9/1/39 |
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