Synaptojanin 1 Modulates Functional Recovery After Incomplete Spinal Cord Injury in Male Apolipoprotein E Epsilon 4 Mice
Apolipoprotein E epsilon 4 (ApoE4) is the second most common variant of ApoE, being present in ?14% of the population. Clinical reports identify ApoE4 as a genetic risk factor for poor outcomes after traumatic spinal cord injury (SCI) and spinal cord diseases such as cervical myelopathy. To date, th...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Mary Ann Liebert
2023-07-01
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| Series: | Neurotrauma Reports |
| Subjects: | |
| Online Access: | https://www.liebertpub.com/doi/full/10.1089/NEUR.2023.0023 |
| _version_ | 1797346183098662912 |
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| author | Carlos A. Toro Jens Hansen Mustafa M. Siddiq Kaitlin Johnson Jiqing Cao Adriana Pero Ravi Iyengar Dongming Cai Christopher P. Cardozo |
| author_facet | Carlos A. Toro Jens Hansen Mustafa M. Siddiq Kaitlin Johnson Jiqing Cao Adriana Pero Ravi Iyengar Dongming Cai Christopher P. Cardozo |
| author_sort | Carlos A. Toro |
| collection | DOAJ |
| description | Apolipoprotein E epsilon 4 (ApoE4) is the second most common variant of ApoE, being present in ?14% of the population. Clinical reports identify ApoE4 as a genetic risk factor for poor outcomes after traumatic spinal cord injury (SCI) and spinal cord diseases such as cervical myelopathy. To date, there is no intervention to promote recovery of function after SCI/spinal cord diseases that is specifically targeted at ApoE4-associated impairment. Studies in the human and mouse brain link ApoE4 to elevated levels of synaptojanin 1 (synj1), a lipid phosphatase that degrades phosphoinositol 4,5-bisphosphate (PIP2) into inositol 4-monophosphate. Synj1 regulates rearrangements of the cytoskeleton as well as endocytosis and trafficking of synaptic vesicles. We report here that, as compared to ApoE3 mice, levels of synj1 messenger RNA and protein were elevated in spinal cords of healthy ApoE4 mice associated with lower PIP2 levels. Using a moderate-severity model of contusion SCI in mice, we found that genetic reduction of synj1 improved locomotor function recovery at 14 days after SCI in ApoE4 mice without altering spared white matter. Genetic reduction of synj1 did not alter locomotor recovery of ApoE3 mice after SCI. Bulk RNA sequencing revealed that at 14 days after SCI in ApoE4 mice, genetic reduction of synj1 upregulated genes involved in glutaminergic synaptic transmission just above and below the lesion. Overall, our findings provide evidence for a link between synj1 to poor outcomes after SCI in ApoE4 mice, up to 14 days post-injury, through mechanisms that may involve the function of excitatory glutaminergic neurons. |
| first_indexed | 2024-03-08T11:29:16Z |
| format | Article |
| id | doaj.art-a46325a807ea45b8958cf91d5ccc95f7 |
| institution | Directory Open Access Journal |
| issn | 2689-288X |
| language | English |
| last_indexed | 2024-03-08T11:29:16Z |
| publishDate | 2023-07-01 |
| publisher | Mary Ann Liebert |
| record_format | Article |
| series | Neurotrauma Reports |
| spelling | doaj.art-a46325a807ea45b8958cf91d5ccc95f72024-01-26T04:37:29ZengMary Ann LiebertNeurotrauma Reports2689-288X2023-07-014146447710.1089/NEUR.2023.0023Synaptojanin 1 Modulates Functional Recovery After Incomplete Spinal Cord Injury in Male Apolipoprotein E Epsilon 4 MiceCarlos A. ToroJens HansenMustafa M. SiddiqKaitlin JohnsonJiqing CaoAdriana PeroRavi IyengarDongming CaiChristopher P. CardozoApolipoprotein E epsilon 4 (ApoE4) is the second most common variant of ApoE, being present in ?14% of the population. Clinical reports identify ApoE4 as a genetic risk factor for poor outcomes after traumatic spinal cord injury (SCI) and spinal cord diseases such as cervical myelopathy. To date, there is no intervention to promote recovery of function after SCI/spinal cord diseases that is specifically targeted at ApoE4-associated impairment. Studies in the human and mouse brain link ApoE4 to elevated levels of synaptojanin 1 (synj1), a lipid phosphatase that degrades phosphoinositol 4,5-bisphosphate (PIP2) into inositol 4-monophosphate. Synj1 regulates rearrangements of the cytoskeleton as well as endocytosis and trafficking of synaptic vesicles. We report here that, as compared to ApoE3 mice, levels of synj1 messenger RNA and protein were elevated in spinal cords of healthy ApoE4 mice associated with lower PIP2 levels. Using a moderate-severity model of contusion SCI in mice, we found that genetic reduction of synj1 improved locomotor function recovery at 14 days after SCI in ApoE4 mice without altering spared white matter. Genetic reduction of synj1 did not alter locomotor recovery of ApoE3 mice after SCI. Bulk RNA sequencing revealed that at 14 days after SCI in ApoE4 mice, genetic reduction of synj1 upregulated genes involved in glutaminergic synaptic transmission just above and below the lesion. Overall, our findings provide evidence for a link between synj1 to poor outcomes after SCI in ApoE4 mice, up to 14 days post-injury, through mechanisms that may involve the function of excitatory glutaminergic neurons.https://www.liebertpub.com/doi/full/10.1089/NEUR.2023.0023contusion SCIfunctional recoveryPIP2Synj1 |
| spellingShingle | Carlos A. Toro Jens Hansen Mustafa M. Siddiq Kaitlin Johnson Jiqing Cao Adriana Pero Ravi Iyengar Dongming Cai Christopher P. Cardozo Synaptojanin 1 Modulates Functional Recovery After Incomplete Spinal Cord Injury in Male Apolipoprotein E Epsilon 4 Mice Neurotrauma Reports contusion SCI functional recovery PIP2 Synj1 |
| title | Synaptojanin 1 Modulates Functional Recovery After Incomplete Spinal Cord Injury in Male Apolipoprotein E Epsilon 4 Mice |
| title_full | Synaptojanin 1 Modulates Functional Recovery After Incomplete Spinal Cord Injury in Male Apolipoprotein E Epsilon 4 Mice |
| title_fullStr | Synaptojanin 1 Modulates Functional Recovery After Incomplete Spinal Cord Injury in Male Apolipoprotein E Epsilon 4 Mice |
| title_full_unstemmed | Synaptojanin 1 Modulates Functional Recovery After Incomplete Spinal Cord Injury in Male Apolipoprotein E Epsilon 4 Mice |
| title_short | Synaptojanin 1 Modulates Functional Recovery After Incomplete Spinal Cord Injury in Male Apolipoprotein E Epsilon 4 Mice |
| title_sort | synaptojanin 1 modulates functional recovery after incomplete spinal cord injury in male apolipoprotein e epsilon 4 mice |
| topic | contusion SCI functional recovery PIP2 Synj1 |
| url | https://www.liebertpub.com/doi/full/10.1089/NEUR.2023.0023 |
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