Striatal cell-type–specific molecular signatures reveal potential therapeutic targets in a model of dystonia
Abnormal dopamine neurotransmission and striatal dysfunction is implicated in many forms of dystonia, yet the underlying molecular processes remain unknown. Here, we identified thousands of dysregulated genes within striatal spiny projection neuron (SPN) subtypes in a genetic mouse model of DOPA-res...
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| Format: | Article |
| Language: | English |
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Elsevier
2025-08-01
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| Series: | Neurobiology of Disease |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996125001974 |
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| author | Kaitlyn M. Roman Ashok R. Dinasarapu Suraj Cherian Xueliang Fan Yuping Donsante Nivetha Aravind C. Savio Chan H.A. Jinnah Ellen J. Hess |
| author_facet | Kaitlyn M. Roman Ashok R. Dinasarapu Suraj Cherian Xueliang Fan Yuping Donsante Nivetha Aravind C. Savio Chan H.A. Jinnah Ellen J. Hess |
| author_sort | Kaitlyn M. Roman |
| collection | DOAJ |
| description | Abnormal dopamine neurotransmission and striatal dysfunction is implicated in many forms of dystonia, yet the underlying molecular processes remain unknown. Here, we identified thousands of dysregulated genes within striatal spiny projection neuron (SPN) subtypes in a genetic mouse model of DOPA-responsive dystonia (DRD), which is caused by gene defects that reduce dopamine neurotransmission. Although changes in mRNA expression were unique to each SPN subtype, abnormal glutamatergic signaling was implicated in each SPN subtype. Indeed, both AMPA and NMDA receptor-mediated currents were enhanced in direct SPNs but diminished in indirect SPNs in DRD mice. The pattern of mRNA dysregulation was distinct from parkinsonism where the dopamine deficit occurs in adults, suggesting that the phenotypic outcome is dependent on both the timing of the dopaminergic deficit and the SPN-specific adaptions. By leveraging these disease-specific molecular signatures, we identified LRRK2 inhibition, among other mechanisms, as a novel therapeutic target for dystonia. |
| format | Article |
| id | doaj-art-382b2f0d93ec4859b7d01717c9974bdd |
| institution | OA Journals |
| issn | 1095-953X |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj-art-382b2f0d93ec4859b7d01717c9974bdd2025-08-20T02:01:51ZengElsevierNeurobiology of Disease1095-953X2025-08-0121210698110.1016/j.nbd.2025.106981Striatal cell-type–specific molecular signatures reveal potential therapeutic targets in a model of dystoniaKaitlyn M. Roman0Ashok R. Dinasarapu1Suraj Cherian2Xueliang Fan3Yuping Donsante4Nivetha Aravind5C. Savio Chan6H.A. Jinnah7Ellen J. Hess8Department of Pharmacology and Chemical Biology, Emory University, Atlanta, GA, USADepartment of Neurology, Emory University, Atlanta, GA, USADepartment of Neuroscience, Northwestern University, Chicago, IL, USADepartment of Pharmacology and Chemical Biology, Emory University, Atlanta, GA, USADepartment of Pharmacology and Chemical Biology, Emory University, Atlanta, GA, USADepartment of Pharmacology and Chemical Biology, Emory University, Atlanta, GA, USADepartment of Neuroscience, Northwestern University, Chicago, IL, USADepartment of Neurology, Emory University, Atlanta, GA, USA; Department of Human Genetics, Emory University, Atlanta, GA, USA; Department of Pediatrics, Emory University, Atlanta, GA, USADepartment of Pharmacology and Chemical Biology, Emory University, Atlanta, GA, USA; Department of Neurology, Emory University, Atlanta, GA, USA; Corresponding author at: Department of Pharmacology and Chemical Biology, Emory University, Atlanta, GA, USA.Abnormal dopamine neurotransmission and striatal dysfunction is implicated in many forms of dystonia, yet the underlying molecular processes remain unknown. Here, we identified thousands of dysregulated genes within striatal spiny projection neuron (SPN) subtypes in a genetic mouse model of DOPA-responsive dystonia (DRD), which is caused by gene defects that reduce dopamine neurotransmission. Although changes in mRNA expression were unique to each SPN subtype, abnormal glutamatergic signaling was implicated in each SPN subtype. Indeed, both AMPA and NMDA receptor-mediated currents were enhanced in direct SPNs but diminished in indirect SPNs in DRD mice. The pattern of mRNA dysregulation was distinct from parkinsonism where the dopamine deficit occurs in adults, suggesting that the phenotypic outcome is dependent on both the timing of the dopaminergic deficit and the SPN-specific adaptions. By leveraging these disease-specific molecular signatures, we identified LRRK2 inhibition, among other mechanisms, as a novel therapeutic target for dystonia.http://www.sciencedirect.com/science/article/pii/S0969996125001974MLi-2RNA-seqParkinson's diseaseTranslatomeMedium spiny neuronD1 dopamine receptor |
| spellingShingle | Kaitlyn M. Roman Ashok R. Dinasarapu Suraj Cherian Xueliang Fan Yuping Donsante Nivetha Aravind C. Savio Chan H.A. Jinnah Ellen J. Hess Striatal cell-type–specific molecular signatures reveal potential therapeutic targets in a model of dystonia Neurobiology of Disease MLi-2 RNA-seq Parkinson's disease Translatome Medium spiny neuron D1 dopamine receptor |
| title | Striatal cell-type–specific molecular signatures reveal potential therapeutic targets in a model of dystonia |
| title_full | Striatal cell-type–specific molecular signatures reveal potential therapeutic targets in a model of dystonia |
| title_fullStr | Striatal cell-type–specific molecular signatures reveal potential therapeutic targets in a model of dystonia |
| title_full_unstemmed | Striatal cell-type–specific molecular signatures reveal potential therapeutic targets in a model of dystonia |
| title_short | Striatal cell-type–specific molecular signatures reveal potential therapeutic targets in a model of dystonia |
| title_sort | striatal cell type specific molecular signatures reveal potential therapeutic targets in a model of dystonia |
| topic | MLi-2 RNA-seq Parkinson's disease Translatome Medium spiny neuron D1 dopamine receptor |
| url | http://www.sciencedirect.com/science/article/pii/S0969996125001974 |
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