Loss of Mitochondrial Ndufs4 in Striatal Medium Spiny Neurons Mediates Progressive Motor Impairment in a Mouse Model of Leigh Syndrome
Inability of mitochondria to generate energy leads to severe and often fatal myoencephalopathies. Among these, Leigh syndrome (LS) is one of the most common childhood mitochondrial diseases; it is characterized by hypotonia, failure to thrive, respiratory insufficiency and progressive mental and mot...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2017-08-01
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| Series: | Frontiers in Molecular Neuroscience |
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| Online Access: | http://journal.frontiersin.org/article/10.3389/fnmol.2017.00265/full |
| _version_ | 1819083557843238912 |
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| author | Byron Chen Jessica Hui Kelsey S. Montgomery Kelsey S. Montgomery Alejandro Gella Alejandro Gella Irene Bolea Irene Bolea Elisenda Sanz Elisenda Sanz Richard D. Palmiter Albert Quintana Albert Quintana Albert Quintana Albert Quintana |
| author_facet | Byron Chen Jessica Hui Kelsey S. Montgomery Kelsey S. Montgomery Alejandro Gella Alejandro Gella Irene Bolea Irene Bolea Elisenda Sanz Elisenda Sanz Richard D. Palmiter Albert Quintana Albert Quintana Albert Quintana Albert Quintana |
| author_sort | Byron Chen |
| collection | DOAJ |
| description | Inability of mitochondria to generate energy leads to severe and often fatal myoencephalopathies. Among these, Leigh syndrome (LS) is one of the most common childhood mitochondrial diseases; it is characterized by hypotonia, failure to thrive, respiratory insufficiency and progressive mental and motor dysfunction, leading to early death. Basal ganglia nuclei, including the striatum, are affected in LS patients. However, neither the identity of the affected cell types in the striatum nor their contribution to the disease has been established. Here, we used a mouse model of LS lacking Ndufs4, a mitochondrial complex I subunit, to confirm that loss of complex I, but not complex II, alters respiration in the striatum. To assess the role of striatal dysfunction in the pathology, we selectively inactivated Ndufs4 in the striatal medium spiny neurons (MSNs), which account for over 95% of striatal neurons. Our results show that lack of Ndufs4 in MSNs causes a non-fatal progressive motor impairment without affecting the cognitive function of mice. Furthermore, no inflammatory responses or neuronal loss were observed up to 6 months of age. Hence, complex I deficiency in MSNs contributes to the motor deficits observed in LS, but not to the neural degeneration, suggesting that other neuronal populations drive the plethora of clinical signs in LS. |
| first_indexed | 2024-12-21T20:34:28Z |
| format | Article |
| id | doaj.art-289cace627004ee8a388e83c0f727295 |
| institution | Directory Open Access Journal |
| issn | 1662-5099 |
| language | English |
| last_indexed | 2024-12-21T20:34:28Z |
| publishDate | 2017-08-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Molecular Neuroscience |
| spelling | doaj.art-289cace627004ee8a388e83c0f7272952022-12-21T18:51:08ZengFrontiers Media S.A.Frontiers in Molecular Neuroscience1662-50992017-08-011010.3389/fnmol.2017.00265288685Loss of Mitochondrial Ndufs4 in Striatal Medium Spiny Neurons Mediates Progressive Motor Impairment in a Mouse Model of Leigh SyndromeByron Chen0Jessica Hui1Kelsey S. Montgomery2Kelsey S. Montgomery3Alejandro Gella4Alejandro Gella5Irene Bolea6Irene Bolea7Elisenda Sanz8Elisenda Sanz9Richard D. Palmiter10Albert Quintana11Albert Quintana12Albert Quintana13Albert Quintana14Department of Biochemistry, Howard Hughes Medical Institute, University of WashingtonSeattle, WA, United StatesCenter for Developmental Therapeutics and Center for Integrative Brain Research, Seattle Children’s Research InstituteSeattle, WA, United StatesCenter for Developmental Therapeutics and Center for Integrative Brain Research, Seattle Children’s Research InstituteSeattle, WA, United StatesInstitut de Neurociències and Department of Cell Biology, Physiology and Immunology, Facultat de Medicina, Universitat Autònoma de BarcelonaBellaterra, SpainCenter for Developmental Therapeutics and Center for Integrative Brain Research, Seattle Children’s Research InstituteSeattle, WA, United StatesInstitut de Neurociències and Department of Cell Biology, Physiology and Immunology, Facultat de Medicina, Universitat Autònoma de BarcelonaBellaterra, SpainCenter for Developmental Therapeutics and Center for Integrative Brain Research, Seattle Children’s Research InstituteSeattle, WA, United StatesInstitut de Neurociències and Department of Cell Biology, Physiology and Immunology, Facultat de Medicina, Universitat Autònoma de BarcelonaBellaterra, SpainCenter for Developmental Therapeutics and Center for Integrative Brain Research, Seattle Children’s Research InstituteSeattle, WA, United StatesInstitut de Neurociències and Department of Cell Biology, Physiology and Immunology, Facultat de Medicina, Universitat Autònoma de BarcelonaBellaterra, SpainDepartment of Biochemistry, Howard Hughes Medical Institute, University of WashingtonSeattle, WA, United StatesDepartment of Biochemistry, Howard Hughes Medical Institute, University of WashingtonSeattle, WA, United StatesCenter for Developmental Therapeutics and Center for Integrative Brain Research, Seattle Children’s Research InstituteSeattle, WA, United StatesInstitut de Neurociències and Department of Cell Biology, Physiology and Immunology, Facultat de Medicina, Universitat Autònoma de BarcelonaBellaterra, SpainDepartment of Pediatrics, University of WashingtonSeattle, WA, United StatesInability of mitochondria to generate energy leads to severe and often fatal myoencephalopathies. Among these, Leigh syndrome (LS) is one of the most common childhood mitochondrial diseases; it is characterized by hypotonia, failure to thrive, respiratory insufficiency and progressive mental and motor dysfunction, leading to early death. Basal ganglia nuclei, including the striatum, are affected in LS patients. However, neither the identity of the affected cell types in the striatum nor their contribution to the disease has been established. Here, we used a mouse model of LS lacking Ndufs4, a mitochondrial complex I subunit, to confirm that loss of complex I, but not complex II, alters respiration in the striatum. To assess the role of striatal dysfunction in the pathology, we selectively inactivated Ndufs4 in the striatal medium spiny neurons (MSNs), which account for over 95% of striatal neurons. Our results show that lack of Ndufs4 in MSNs causes a non-fatal progressive motor impairment without affecting the cognitive function of mice. Furthermore, no inflammatory responses or neuronal loss were observed up to 6 months of age. Hence, complex I deficiency in MSNs contributes to the motor deficits observed in LS, but not to the neural degeneration, suggesting that other neuronal populations drive the plethora of clinical signs in LS.http://journal.frontiersin.org/article/10.3389/fnmol.2017.00265/fullmitochondrial diseasemouse geneticsstriatumbehavioranimalmedium spiny neuron |
| spellingShingle | Byron Chen Jessica Hui Kelsey S. Montgomery Kelsey S. Montgomery Alejandro Gella Alejandro Gella Irene Bolea Irene Bolea Elisenda Sanz Elisenda Sanz Richard D. Palmiter Albert Quintana Albert Quintana Albert Quintana Albert Quintana Loss of Mitochondrial Ndufs4 in Striatal Medium Spiny Neurons Mediates Progressive Motor Impairment in a Mouse Model of Leigh Syndrome Frontiers in Molecular Neuroscience mitochondrial disease mouse genetics striatum behavior animal medium spiny neuron |
| title | Loss of Mitochondrial Ndufs4 in Striatal Medium Spiny Neurons Mediates Progressive Motor Impairment in a Mouse Model of Leigh Syndrome |
| title_full | Loss of Mitochondrial Ndufs4 in Striatal Medium Spiny Neurons Mediates Progressive Motor Impairment in a Mouse Model of Leigh Syndrome |
| title_fullStr | Loss of Mitochondrial Ndufs4 in Striatal Medium Spiny Neurons Mediates Progressive Motor Impairment in a Mouse Model of Leigh Syndrome |
| title_full_unstemmed | Loss of Mitochondrial Ndufs4 in Striatal Medium Spiny Neurons Mediates Progressive Motor Impairment in a Mouse Model of Leigh Syndrome |
| title_short | Loss of Mitochondrial Ndufs4 in Striatal Medium Spiny Neurons Mediates Progressive Motor Impairment in a Mouse Model of Leigh Syndrome |
| title_sort | loss of mitochondrial ndufs4 in striatal medium spiny neurons mediates progressive motor impairment in a mouse model of leigh syndrome |
| topic | mitochondrial disease mouse genetics striatum behavior animal medium spiny neuron |
| url | http://journal.frontiersin.org/article/10.3389/fnmol.2017.00265/full |
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