CDR1as regulates α-synuclein-mediated ischemic brain damage by controlling miR-7 availability
Transient focal ischemia decreased microRNA-7 (miR-7) levels, leading to derepression of its major target α-synuclein (α-Syn) that promotes secondary brain damage. Circular RNA CDR1as is known to regulate miR-7 abundance and function. Hence, we currently evaluated its functional significance after f...
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| Format: | Article |
| Language: | English |
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Elsevier
2023-03-01
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| Series: | Molecular Therapy: Nucleic Acids |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2162253122003146 |
| _version_ | 1811182569997205504 |
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| author | Suresh L. Mehta Anil K. Chokkalla Saivenkateshkomal Bathula Vijay Arruri Bharath Chelluboina Raghu Vemuganti |
| author_facet | Suresh L. Mehta Anil K. Chokkalla Saivenkateshkomal Bathula Vijay Arruri Bharath Chelluboina Raghu Vemuganti |
| author_sort | Suresh L. Mehta |
| collection | DOAJ |
| description | Transient focal ischemia decreased microRNA-7 (miR-7) levels, leading to derepression of its major target α-synuclein (α-Syn) that promotes secondary brain damage. Circular RNA CDR1as is known to regulate miR-7 abundance and function. Hence, we currently evaluated its functional significance after focal ischemia. Transient middle cerebral artery occlusion (MCAO) in adult mice significantly downregulated both CDR1as and miR-7 levels in the peri-infarct cortex between 3 and 72 h of reperfusion. Interestingly, neither pri-miR-7a nor 7b was altered in the ischemic brain. Intracerebral injection of an AAV9 vector containing a CDR1as gene significantly increased CDR1as levels by 21 days that persisted up to 4 months without inducing any observable toxicity in both sham and MCAO groups. Following transient MCAO, there was a significant increase in miR-7 levels and CDR1as binding to Ago2/miR-7 in the peri-infarct cortex of AAV9-CDR1as cohort compared with AAV9-Control cohort at 1 day of reperfusion. CDR1as overexpression significantly suppressed post-stroke α-Syn protein induction, promoted motor function recovery, decreased infarct size, and curtailed the markers of apoptosis, autophagy mitochondrial fragmentation, and inflammation in the post-stroke brain compared with AAV9-Control-treated cohort. Overall, our findings imply that CDR1as reconstitution is neuroprotective after stroke, probably by protecting miR-7 and preventing α-Syn-mediated neuronal death. |
| first_indexed | 2024-04-11T09:34:01Z |
| format | Article |
| id | doaj.art-012ecab810034e409ead9709e5e74178 |
| institution | Directory Open Access Journal |
| issn | 2162-2531 |
| language | English |
| last_indexed | 2024-04-11T09:34:01Z |
| publishDate | 2023-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Nucleic Acids |
| spelling | doaj.art-012ecab810034e409ead9709e5e741782022-12-22T04:31:46ZengElsevierMolecular Therapy: Nucleic Acids2162-25312023-03-01315767CDR1as regulates α-synuclein-mediated ischemic brain damage by controlling miR-7 availabilitySuresh L. Mehta0Anil K. Chokkalla1Saivenkateshkomal Bathula2Vijay Arruri3Bharath Chelluboina4Raghu Vemuganti5Department of Neurological Surgery, University of Wisconsin-Madison, Madison, WI 53792, USA; Corresponding author Suresh L Mehta, PhD, Department of Neurological Surgery, University of Wisconsin-Madison, Mail code CSC-8660, 600 Highland Ave, Madison, WI 53792, USA.Department of Neurological Surgery, University of Wisconsin-Madison, Madison, WI 53792, USADepartment of Neurological Surgery, University of Wisconsin-Madison, Madison, WI 53792, USADepartment of Neurological Surgery, University of Wisconsin-Madison, Madison, WI 53792, USADepartment of Neurological Surgery, University of Wisconsin-Madison, Madison, WI 53792, USADepartment of Neurological Surgery, University of Wisconsin-Madison, Madison, WI 53792, USA; William S. Middleton Veterans Administration Hospital, Madison, WI 53792, USATransient focal ischemia decreased microRNA-7 (miR-7) levels, leading to derepression of its major target α-synuclein (α-Syn) that promotes secondary brain damage. Circular RNA CDR1as is known to regulate miR-7 abundance and function. Hence, we currently evaluated its functional significance after focal ischemia. Transient middle cerebral artery occlusion (MCAO) in adult mice significantly downregulated both CDR1as and miR-7 levels in the peri-infarct cortex between 3 and 72 h of reperfusion. Interestingly, neither pri-miR-7a nor 7b was altered in the ischemic brain. Intracerebral injection of an AAV9 vector containing a CDR1as gene significantly increased CDR1as levels by 21 days that persisted up to 4 months without inducing any observable toxicity in both sham and MCAO groups. Following transient MCAO, there was a significant increase in miR-7 levels and CDR1as binding to Ago2/miR-7 in the peri-infarct cortex of AAV9-CDR1as cohort compared with AAV9-Control cohort at 1 day of reperfusion. CDR1as overexpression significantly suppressed post-stroke α-Syn protein induction, promoted motor function recovery, decreased infarct size, and curtailed the markers of apoptosis, autophagy mitochondrial fragmentation, and inflammation in the post-stroke brain compared with AAV9-Control-treated cohort. Overall, our findings imply that CDR1as reconstitution is neuroprotective after stroke, probably by protecting miR-7 and preventing α-Syn-mediated neuronal death.http://www.sciencedirect.com/science/article/pii/S2162253122003146MT: Noncoding RNAsischemiaα-synucleinmotor function recoverypathological changes |
| spellingShingle | Suresh L. Mehta Anil K. Chokkalla Saivenkateshkomal Bathula Vijay Arruri Bharath Chelluboina Raghu Vemuganti CDR1as regulates α-synuclein-mediated ischemic brain damage by controlling miR-7 availability Molecular Therapy: Nucleic Acids MT: Noncoding RNAs ischemia α-synuclein motor function recovery pathological changes |
| title | CDR1as regulates α-synuclein-mediated ischemic brain damage by controlling miR-7 availability |
| title_full | CDR1as regulates α-synuclein-mediated ischemic brain damage by controlling miR-7 availability |
| title_fullStr | CDR1as regulates α-synuclein-mediated ischemic brain damage by controlling miR-7 availability |
| title_full_unstemmed | CDR1as regulates α-synuclein-mediated ischemic brain damage by controlling miR-7 availability |
| title_short | CDR1as regulates α-synuclein-mediated ischemic brain damage by controlling miR-7 availability |
| title_sort | cdr1as regulates α synuclein mediated ischemic brain damage by controlling mir 7 availability |
| topic | MT: Noncoding RNAs ischemia α-synuclein motor function recovery pathological changes |
| url | http://www.sciencedirect.com/science/article/pii/S2162253122003146 |
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