Generic placeholder image

Current Neurovascular Research

Editor-in-Chief

ISSN (Print): 1567-2026
ISSN (Online): 1875-5739

Research Article

Combined Transcriptomic and Proteomic Analyses of Cerebral Frontal Lobe Tissue Identified RNA Metabolism Dysregulation as One Potential Pathogenic Mechanism in Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL)

Author(s): Marie-Françoise Ritz*, Paul Jenoe, Leo Bonati, Stefan Engelter, Philippe Lyrer and Nils Peters

Volume 16, Issue 5, 2019

Page: [481 - 493] Pages: 13

DOI: 10.2174/1567202616666191023111059

open access plus

Abstract

Background: Cerebral small vessel disease (SVD) is an important cause of stroke and vascular cognitive impairment (VCI), leading to subcortical ischemic vascular dementia. As a hereditary form of SVD with early onset, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) represents a pure form of SVD and may thus serve as a model disease for SVD. To date, underlying molecular mechanisms linking vascular pathology and subsequent neuronal damage in SVD are incompletely understood.

Objective: We performed comparative transcriptional profiling microarray and proteomic analyses on post-mortem frontal lobe specimen from 2 CADASIL patients and 5 non neurologically diseased controls in order to identify dysregulated pathways potentially involved in the development of tissue damage in CADASIL.

Methods: Transcriptional microarray analysis of material extracted from frontal grey and white matter (WM) identified subsets of up- or down-regulated genes enriched into biological pathways mostly in WM areas. Proteomic analysis of these regions also highlighted cellular processes identified by dysregulated proteins.

Results: Discrepancies between proteomic and transcriptomic data were observed, but a number of pathways were commonly associated with genes and corresponding proteins, such as: “ribosome” identified by upregulated genes and proteins in frontal cortex or “spliceosome” associated with down-regulated genes and proteins in frontal WM.

Conclusion: This latter finding suggests that defective expression of spliceosomal components may alter widespread splicing profile, potentially inducing expression abnormalities that could contribute to cerebral WM damage in CADASIL.

Keywords: CADASIL, transcriptomic, proteomic, pathomechanisms, spliceosome, ribosome.

[1]
Pantoni L. Cerebral small vessel disease: From pathogenesis and clinical characteristics to therapeutic challenges. Lancet Neurol 2010; 9(7): 689-701.
[http://dx.doi.org/10.1016/S1474-4422(10)70104-6] [PMID: 20610345]
[2]
Chabriat H, Joutel A, Dichgans M, Tournier-Lasserve E, Bousser MG. Cadasil. Lancet Neurol 2009; 8(7): 643-53.
[http://dx.doi.org/10.1016/S1474-4422(09)70127-9] [PMID: 19539236]
[3]
Joutel A, Corpechot C, Ducros A, et al. Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia. Nature 1996; 383(6602): 707-10.
[http://dx.doi.org/10.1038/383707a0] [PMID: 8878478]
[4]
Holtmannspötter M, Peters N, Opherk C, et al. Diffusion magnetic resonance histograms as a surrogate marker and predictor of disease progression in CADASIL: A two-year follow-up study. Stroke 2005; 36(12): 2559-65.
[http://dx.doi.org/10.1161/01.STR.0000189696.70989.a4] [PMID: 16269644]
[5]
Peters N, Holtmannspötter M, Opherk C, et al. Brain volume changes in CADASIL: A serial MRI study in pure subcortical ischemic vascular disease. Neurology 2006; 66(10): 1517-22.
[http://dx.doi.org/10.1212/01.wnl.0000216271.96364.50] [PMID: 16717211]
[6]
Erkinjuntti T, Gauthier S. The concept of vascular cognitive impairment. Front Neurol Neurosci 2009; 24: 79-85.
[http://dx.doi.org/10.1159/000197886] [PMID: 19182465]
[7]
Tikka S, Mykkänen K, Ruchoux MM, et al. Congruence between NOTCH3 mutations and GOM in 131 CADASIL patients. Brain 2009; 132(Pt 4): 933-9.
[http://dx.doi.org/10.1093/brain/awn364] [PMID: 19174371]
[8]
Ruchoux MM, Guerouaou D, Vandenhaute B, Pruvo JP, Vermersch P, Leys D. Systemic vascular smooth muscle cell impairment in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Acta Neuropathol 1995; 89(6): 500-12.
[http://dx.doi.org/10.1007/BF00571504] [PMID: 7676806]
[9]
Zhang X, Meng H, Blaivas M, et al. Von Willebrand Factor permeates small vessels in CADASIL and inhibits smooth muscle gene expression. Transl Stroke Res 2012; 3(1): 138-45.
[http://dx.doi.org/10.1007/s12975-011-0112-2] [PMID: 22639698]
[10]
Østergaard L, Engedal TS, Moreton F, et al. Cerebral small vessel disease: Capillary pathways to stroke and cognitive decline. J Cereb Blood Flow Metab 2016; 36(2): 302-25.
[http://dx.doi.org/10.1177/0271678X15606723] [PMID: 26661176]
[11]
Wiseman S, Marlborough F, Doubal F, Webb DJ, Wardlaw J. Blood markers of coagulation, fibrinolysis, endothelial dysfunction and inflammation in lacunar stroke versus non-lacunar stroke and non-stroke: Systematic review and meta-analysis. Cerebrovasc Dis 2014; 37(1): 64-75.
[http://dx.doi.org/10.1159/000356789] [PMID: 24401164]
[12]
Ritz MF, Grond-Ginsbach C, Kloss M, et al. Identification of inflammatory, metabolic, and cell survival pathways contributing to cerebral small vessel disease by postmortem gene expression microarray. Curr Neurovasc Res 2016; 13(1): 58-67.
[http://dx.doi.org/10.2174/1567202612666151027151025] [PMID: 26503025]
[13]
Vogel C, Marcotte EM. Insights into the regulation of protein abundance from proteomic and transcriptomic analyses. Nat Rev Genet 2012; 13(4): 227-32.
[http://dx.doi.org/10.1038/nrg3185] [PMID: 22411467]
[14]
Ritz MF, Grond-Ginsbach C, Fluri F, et al. Cerebral small vessel disease is associated with dysregulation in the ubiquitin proteasome system and other major cellular pathways in specific brain regions. Neurodegener Dis 2017; 17(6): 261-75.
[http://dx.doi.org/10.1159/000478529] [PMID: 28810250]
[15]
Wiśniewski JR, Zougman A, Nagaraj N, Mann M. Universal sample preparation method for proteome analysis. Nat Methods 2009; 6(5): 359-62.
[http://dx.doi.org/10.1038/nmeth.1322] [PMID: 19377485]
[16]
Ban S, Wang H, Wang M, et al. Diffuse tract damage in CADASIL is correlated with global cognitive impairment. Eur Neurol 2019. [Epub ahead of print]
[http://dx.doi.org/10.1159/000501612] [PMID: 31484188]
[17]
Chiang HY, Korshunov VA, Serour A, Shi F, Sottile J. Fibronectin is an important regulator of flow-induced vascular remodeling. Arterioscler Thromb Vasc Biol 2009; 29(7): 1074-9.
[http://dx.doi.org/10.1161/ATVBAHA.108.181081] [PMID: 19407246]
[18]
Joutel A, Haddad I, Ratelade J, Nelson MT. Perturbations of the cerebrovascular matrisome: A convergent mechanism in small vessel disease of the brain? J Cereb Blood Flow Metab (Nihongoban) 2015. [Epub ahead of print]
[19]
Kast J, Hanecker P, Beaufort N, et al. Sequestration of latent TGF-β binding protein 1 into CADASIL-related Notch3-ECD deposits. Acta Neuropathol Commun 2014; 2(1): 96.
[http://dx.doi.org/10.1186/s40478-014-0096-8] [PMID: 25190493]
[20]
Conley CA. Leiomodin and tropomodulin in smooth muscle. Am J Physiol Cell Physiol 2001; 280(6): C1645-56.
[http://dx.doi.org/10.1152/ajpcell.2001.280.6.C1645] [PMID: 11350761]
[21]
Van de Wouwer M, Collen D, Conway EM. Thrombomodulin-protein C-EPCR system: Integrated to regulate coagulation and inflammation. Arterioscler Thromb Vasc Biol 2004; 24(8): 1374-83.
[http://dx.doi.org/10.1161/01.ATV.0000134298.25489.92] [PMID: 15178554]
[22]
Bonnefoy A, Moura R, Hoylaerts MF. The evolving role of thrombospondin-1 in hemostasis and vascular biology. Cell Mol Life Sci 2008; 65(5): 713-27.
[http://dx.doi.org/10.1007/s00018-007-7487-y] [PMID: 18193161]
[23]
Kahn ML, Zheng YW, Huang W, et al. A dual thrombin receptor system for platelet activation. Nature 1998; 394(6694): 690-4.
[http://dx.doi.org/10.1038/29325] [PMID: 9716134]
[24]
Marrif H, Juurlink BH. Astrocytes respond to hypoxia by increasing glycolytic capacity. J Neurosci Res 1999; 57(2): 255-60.
[http://dx.doi.org/10.1002/(SICI)1097-4547(19990715)57:2<255:AID-JNR11>3.0.CO;2-6] [PMID: 10398303]
[25]
Fünfschilling U, Supplie LM, Mahad D, et al. Glycolytic oligodendrocytes maintain myelin and long-term axonal integrity. Nature 2012; 485(7399): 517-21.
[http://dx.doi.org/10.1038/nature11007] [PMID: 22622581]
[26]
Denko N, Schindler C, Koong A, Laderoute K, Green C, Giaccia A. Epigenetic regulation of gene expression in cervical cancer cells by the tumor microenvironment. Clin Cancer Res 2000; 6(2): 480-7.
[27]
Gimm T, Wiese M, Teschemacher B, et al. Hypoxia-inducible protein 2 is a novel lipid droplet protein and a specific target gene of hypoxia-inducible factor-1. FASEB J 2010; 24(11): 4443-58.
[http://dx.doi.org/10.1096/fj.10-159806] [PMID: 20624928]
[28]
Schwarzer R, Tondera D, Arnold W, Giese K, Klippel A, Kaufmann J. REDD1 integrates hypoxia-mediated survival signaling downstream of phosphatidylinositol 3-kinase. Oncogene 2005; 24(7): 1138-49.
[http://dx.doi.org/10.1038/sj.onc.1208236] [PMID: 15592522]
[29]
Sofer A, Lei K, Johannessen CM, Ellisen LW. Regulation of mTOR and cell growth in response to energy stress by REDD1. Mol Cell Biol 2005; 25(14): 5834-45.
[http://dx.doi.org/10.1128/MCB.25.14.5834-5845.2005] [PMID: 15988001]
[30]
Faustino NA, Cooper TA. Pre-mRNA splicing and human disease. Genes Dev 2003; 17(4): 419-37.
[http://dx.doi.org/10.1101/gad.1048803] [PMID: 12600935]
[31]
Zhang X, Chen S, Yoo S, et al. Mutation in nuclear pore component NUP155 leads to atrial fibrillation and early sudden cardiac death. Cell 2008; 135(6): 1017-27.
[http://dx.doi.org/10.1016/j.cell.2008.10.022] [PMID: 19070573]
[32]
Kishore S, Khanna A, Zhang Z, et al. The snoRNA MBII-52 (SNORD 115) is processed into smaller RNAs and regulates alternative splicing. Hum Mol Genet 2010; 19(7): 1153-64.
[http://dx.doi.org/10.1093/hmg/ddp585] [PMID: 20053671]
[33]
Falaleeva M, Surface J, Shen M, de la Grange P, Stamm S. SNORD116 and SNORD115 change expression of multiple genes and modify each other’s activity. Gene 2015; 572(2): 266-73.
[http://dx.doi.org/10.1016/j.gene.2015.07.023] [PMID: 26220404]
[34]
Gibbons A, Udawela M, Dean B. Non-coding RNA as novel players in the pathophysiology of schizophrenia. Noncoding RNA 2018; 4(2) E11
[http://dx.doi.org/10.3390/ncrna4020011] [PMID: 29657307]
[35]
Turi Z, Lacey M, Mistrik M, Moudry P. Impaired ribosome biogenesis: Mechanisms and relevance to cancer and aging. Aging (Albany NY) 2019; 11(8): 2512-40.
[http://dx.doi.org/10.18632/aging.101922] [PMID: 31026227]
[36]
Ping S, Qiu X, Gonzalez-Toledo ME, Liu X, Zhao LR. Stem cell factor in combination with granulocyte colony-stimulating factor reduces cerebral capillary thrombosis in a mouse model of CADASIL. Cell Transplant 2018; 27(4): 637-47.
[http://dx.doi.org/10.1177/0963689718766460] [PMID: 29871518]
[37]
Ghezali L, Capone C, Baron-Menguy C, et al. Notch3ECD immunotherapy improves cerebrovascular responses in CADASIL mice. Ann Neurol 2018; 84(2): 246-59.
[http://dx.doi.org/10.1002/ana.25284] [PMID: 30014602]
[38]
Ping S, Qiu X, Kyle M, Hughes K, Longo J, Zhao LR. Stem cell factor and granulocyte colony-stimulating factor promote brain repair and improve cognitive function through VEGF-A in a mouse model of CADASIL. Neurobiol Dis 2019; 132 104561
[http://dx.doi.org/10.1016/j.nbd.2019.104561] [PMID: 31376480]
[39]
Duering M, Konieczny MJ, Tiedt S, et al. Serum neurofilament light chain levels are related to small vessel disease burden. J Stroke 2018; 20(2): 228-38.
[http://dx.doi.org/10.5853/jos.2017.02565] [PMID: 29886723]

© 2024 Bentham Science Publishers | Privacy Policy