Abstract
RAB7, a member of RAS oncogene family–like 1 (RAB7L1), is a GTPase belonging to the Rab family and acts as an upstream regulator to regulate the kinase activity of leucine-rich repeat kinase 2 (LRRK2). Although LRRK2 has been shown to aggravate secondary brain injury (SBI) after intracerebral hemorrhage (ICH), it is unknown whether RAB7L1 is also involved in this process. The purpose of the present study was to investigate the role of RAB7L1 in ICH-induced SBI in vivo. Autologous blood was injected into adult male Sprague-Dawley rats to induce an ICH model in vivo. The results showed that the protein levels of RAB7L1 increased after ICH. Overexpression of RAB7L1 induced neuronal apoptosis and damage, as demonstrated by TUNEL-positive and FJB-positive cells, and exacerbated ICH-induced learning and cognitive dysfunctions; in contrast, downregulation of RAB7L1 via RNA interference yielded comparatively opposite changes in these parameters. In summary, this study demonstrates that RAB7L1 promotes SBI after ICH and may represent a potential target for ICH therapy.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Boltze J et al (2019) Lesional and perilesional tissue characterization by automated image processing in a novel gyrencephalic animal model of peracute intracerebral hemorrhage. J Cereb Blood Flow Metab 39:2521–2535. https://doi.org/10.1177/0271678X18802119
Cao J et al (2018) Leucine-rich repeat kinase 2 aggravates secondary brain injury induced by intracerebral hemorrhage in rats by regulating the P38 MAPK/Drosha pathway. Neurobiol Dis 119:53–64. https://doi.org/10.1016/j.nbd.2018.07.024
Cheng X, Ander BP, Jickling GC, Zhan X, Hull H, Sharp FR, Stamova B (2020) MicroRNA and their target mRNAs change expression in whole blood of patients after intracerebral hemorrhage. J Cereb Blood Flow Metab 40:775–786. https://doi.org/10.1177/0271678X19839501
Cookson MR (2010) The role of leucine-rich repeat kinase 2 (LRRK2) in Parkinson’s disease. Nat Rev Neurosci 11:791–797. https://doi.org/10.1038/nrn2935
Cordonnier C, Demchuk A, Ziai W, Anderson CS (2018) Intracerebral haemorrhage: current approaches to acute management. Lancet 392:1257–1268. https://doi.org/10.1016/s0140-6736(18)31878-6
Dmytriyeva O et al (2012) The metastasis-promoting S100A4 protein confers neuroprotection in brain injury. Nat Commun 3:1197. https://doi.org/10.1038/ncomms2202
Eguchi T et al (2018) LRRK2 and its substrate Rab GTPases are sequentially targeted onto stressed lysosomes and maintain their homeostasis. Proc Natl Acad Sci U S A 115:E9115–e9124. https://doi.org/10.1073/pnas.1812196115
Fuji RN et al (2015) Effect of selective LRRK2 kinase inhibition on nonhuman primate lung. Sci Transl Med 7:273ra215. https://doi.org/10.1126/scitranslmed.aaa3634
Fujimoto T, Kuwahara T, Eguchi T, Sakurai M, Komori T, Iwatsubo T (2018) Parkinson’s disease-associated mutant LRRK2 phosphorylates Rab7L1 and modifies trans-Golgi morphology. Biochem Biophys Res Commun 495:1708–1715. https://doi.org/10.1016/j.bbrc.2017.12.024
He T, Wang J, Wang X, Deng W, Jiang H, Xie J, Sun P (2017) Association between PARK16 and Parkinson’s disease: a meta-analysis. Neurosci Lett 657:179–188. https://doi.org/10.1016/j.neulet.2017.08.022
Jolink WM et al (2019) Contrast leakage distant from the hematoma in patients with spontaneous ICH: a 7 T MRI study. J Cereb Blood Flow Metab:271678X19852876. https://doi.org/10.1177/0271678X19852876
Khaligh A, Goudarzian M, Moslem A, Mehrtash A, Jamshidi J, Darvish H, Emamalizadeh B (2017) RAB7L1 promoter polymorphism and risk of Parkinson’s disease; a case-control study. Neurol Res 39:468–471. https://doi.org/10.1080/01616412.2017.1297558
Liu Z, Bryant N, Kumaran R, Beilina A, Abeliovich A, Cookson MR, West AB (2018) LRRK2 phosphorylates membrane-bound Rabs and is activated by GTP-bound Rab7L1 to promote recruitment to the trans-Golgi network. Hum Mol Genet 27:385–395. https://doi.org/10.1093/hmg/ddx410
MacLeod D, Dowman J, Hammond R, Leete T, Inoue K, Abeliovich A (2006) The familial Parkinsonism gene LRRK2 regulates neurite process morphology. Neuron 52:587–593. https://doi.org/10.1016/j.neuron.2006.10.008
Massmann S, Schurmann A, Joost HG (1997) Cloning of two splicing variants of the novel Ras-related GTPase Rab29 which is predominantly expressed in kidney. Biochim Biophys Acta 1352:48–55. https://doi.org/10.1016/s0167-4781(97)00014-6
Purlyte E, Dhekne HS, Sarhan AR (2018) Rab29 activation of the Parkinson’s disease-associated LRRK2 kinase. EMBO J 37:1–18. https://doi.org/10.15252/embj.201798099
Qureshi AI, Mendelow AD, Hanley DF (2009) Intracerebral haemorrhage. Lancet 373:1632–1644. https://doi.org/10.1016/s0140-6736(09)60371-8
Shimizu F et al (1997) Cloning and chromosome assignment to 1q32 of a human cDNA (RAB7L1) encoding a small GTP-binding protein, a member of the RAS superfamily. Cytogenet Cell Genet 77:261–263. https://doi.org/10.1159/000134591
Smith WW, Pei Z, Jiang H, Dawson VL, Dawson TM, Ross CA (2006) Kinase activity of mutant LRRK2 mediates neuronal toxicity. Nat Neurosci 9:1231–1233. https://doi.org/10.1038/nn1776
Spano S, Liu X, Galan JE (2011) Proteolytic targeting of Rab29 by an effector protein distinguishes the intracellular compartments of human-adapted and broad-host Salmonella. Proc Natl Acad Sci U S A 108:18418–18423. https://doi.org/10.1073/pnas.1111959108
Stamova B et al (2019) The intracerebral hemorrhage blood transcriptome in humans differs from the ischemic stroke and vascular risk factor control blood transcriptomes. J Cereb Blood Flow Metab 39:1818–1835. https://doi.org/10.1177/0271678X18769513
Tao C, Keep RF, Xi G, Hua Y (2019) CD47 blocking antibody accelerates hematoma clearance after intracerebral hemorrhage in aged rats. Transl Stroke Res. https://doi.org/10.1007/s12975-019-00745-4
Urday S et al (2015) Targeting secondary injury in intracerebral haemorrhage--perihaematomal oedema. Nat Rev Neurol 11:111–122. https://doi.org/10.1038/nrneurol.2014.264
Wallings R, Manzoni C, Bandopadhyay R (2015) Cellular processes associated with LRRK2 function and dysfunction. FEBS J 282:2806–2826. https://doi.org/10.1111/febs.13305
Wang S et al (2014) A role of Rab29 in the integrity of the trans-Golgi network and retrograde trafficking of mannose-6-phosphate receptor. PLoS One 9:e96242. https://doi.org/10.1371/journal.pone.0096242
Wang Z et al (2019) Treatment of secondary brain injury by perturbing postsynaptic density protein-95-NMDA receptor interaction after intracerebral hemorrhage in rats. J Cereb Blood Flow Metab 39:1588–1601. https://doi.org/10.1177/0271678X18762637
Wei J, Wang M, Jing C, Keep RF, Hua Y, Xi G (2020) Multinucleated giant cells in experimental intracerebral hemorrhage. Transl Stroke Res. https://doi.org/10.1007/s12975-020-00790-4
West AB (2017) Achieving neuroprotection with LRRK2 kinase inhibitors in Parkinson disease. Exp Neurol 298:236–245. https://doi.org/10.1016/j.expneurol.2017.07.019
West AB et al (2007) Parkinson’s disease-associated mutations in LRRK2 link enhanced GTP-binding and kinase activities to neuronal toxicity. Hum Mol Genet 16:223–232. https://doi.org/10.1093/hmg/ddl471
Zhang P et al (2019a) Exploration of MST1-mediated secondary brain injury induced by Intracerebral hemorrhage in rats via hippo signaling pathway. Transl Stroke Res 10:729–743. https://doi.org/10.1007/s12975-019-00702-1
Zhang S et al (2020) AAV/BBB-mediated gene transfer of CHIP attenuates brain injury following experimental intracerebral hemorrhage. Transl Stroke Res 11:296–309. https://doi.org/10.1007/s12975-019-00715-w
Zhang Z, Cho S, Rehni AK, Quero HN, Dave KR, Zhao W (2019b) Automated assessment of hematoma volume of rodents subjected to experimental Intracerebral hemorrhagic stroke by Bayes segmentation approach. Transl Stroke Res. https://doi.org/10.1007/s12975-019-00754-3
Zhang Z et al (2018) Glutathione peroxidase 4 participates in secondary brain injury through mediating ferroptosis in a rat model of intracerebral hemorrhage. Brain Res 1701:112–125. https://doi.org/10.1016/j.brainres.2018.09.012
Zhou T, Wang H, Shen J, Li W, Cao M, Hong Y, Cao M (2019) The p35/CDK5 signaling is regulated by p75NTR in neuronal apoptosis after intracerebral hemorrhage. J Cell Physiol. https://doi.org/10.1002/jcp.28244
Funding
This work was supported by the National Key R&D Program of China (No. 2018YFC1312600 and 2018YFC1312601), Project of Jiangsu Provincial Medical Innovation Team (No. CXTDA2017003), Jiangsu Provincial Medical Youth Talent (No. QNRC2016728), Suzhou Key Medical Centre (No. Szzx201501), Scientific Department of Jiangsu Province (No. BE2017656), the Natural Science Foundation of Jiangsu Province under grant (No. BK20180204 & No.BK20170363), and the Suzhou Government (LCZX201601).
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Conflict of Interest
The authors declare that they have no conflicts of interest.
Additional information
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Tan, X., Wei, Y., Cao, J. et al. RAB7L1 Participates in Secondary Brain Injury Induced by Experimental Intracerebral Hemorrhage in Rats. J Mol Neurosci 71, 9–18 (2021). https://doi.org/10.1007/s12031-020-01619-3
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12031-020-01619-3