He graduated with honors in Medicine at the University of Milan and achieved the Board Certification in Neurology. He works at the “Carlo Besta” Neurological Institute of Milan as staff neurologist since 2010. He was also Honorary Visiting Research Fellow at the Western Infirmary General Glasgow Hospital, Clinical Observer at the Barrow Neurological Institute of Phoenix, Arizona and Clinical expert for the Luigi Bocconi University of Milan.
In 2009 he was awarded the International Award Friends of Milan for Youth – Silver Plate of the President of the Republic and the Lombardy Region Gold Medal awarded for Neurology-Neurobiology and in 2017 he obtained the national scientific qualification for professor of NEUROLOGY.
His scientific interests are aimed at clinical research in the field of cerebrovascular diseases, in particular the “non-Mendelian” genetics and the possible use of stem cells, publishing his works on Nature Genetics, Lancet Neurology, Annals of Neurology, Stroke, Neurology, Cochrane Database of Systematic Reviews. In 2016 he organized in Milan the “20th Workshop of the International Stroke Genetics Consortium” which was attended by more than 80 researchers from all over the world. It obtained from the Ministry of Health total funding of € 375,000 for 2 targeted research projects.
Role of Ryanodine Receptor type 3 (RyR3) in ischemic stroke
Track: Clinical Neuroscience
Tutor: Fabrizio Tagliavini
Supervisor: Eugenio Parati
AIMS: This project aims at investigating the role of RYR3 in cerebral ischemia from genetic, cellular and functional point of view and replicating our GWAS findings in other ischemic stroke cohorts with outcome data.
BACKGROUND: Ischemic stroke is the fourth leading cause of death and the leading cause of acquired disability in developed countries. To date, the possibilities for effective treatments are quite limited. Ischemic stroke is the end result of many different pathophysiological processes, which result in multiple subtypes (mostly large-artery stroke, cardioembolic stroke and small-vessel disease). Identification of individual stroke subtypes requires a detailed clinical work-up, but even with appropriate investigations, an underlying pathology cannot be found in 30% of patients. This heterogeneity implies that different pathological mechanisms are responsible for different subtypes of stroke; identification of genetic variations that are associated with these subtypes might provide insight into these mechanisms and provide opportunities to develop more-effective therapeutic approaches [Markus 2014].
The first genomewide association study conducted in a cohort of Italian patients with ischemic stroke, held in the Cerebrovascular Disease Department at Besta Institute, found a statistically significant association with a coding single nucleotide polymorphism (SNP) in the Ryanodine Receptor type 3 (RyR3) gene on chromosome 15. Since this association was not replicated in other cohorts with acute ischemic stroke cases [Traylor 2012, data not published], we thought that this could be ascribed to the peculiarity of our cohort, composed mainly of stroke survivors with good outcome. This suggested us the possibility that RYR3 could influence stroke outcome, which was confirmed when we found a statistically significant association between 3 SNPs in the RYR3 locus and stroke outcome at 3 months in the SiGN cohort (NINDS Stroke Genetics Network) [Sammali 2017].
RYR3 is expressed in the brain and it is a good candidate gene for stroke recovery: controlling the mobilization of intracellular calcium, it is a key regulator in the neurons of functions ranging from gene expression,adaptive responses, synaptic plasticity and neuronal death, processes that play a key role in post-stroke recovery. However, to date, the role of RYR3 in cerebral ischemia is poorly understood [Lanner 2010].
METHODS: Genetic study: – Resequencing of the RYR3 gene region in ischemic stroke patients by next-generation sequencing; – Deep investigation of the genetic variability across the RYR3 genomic region; – Replication of GWAS-identified SNP associated with ischemic stroke in the Italian cohort (and/or other relevant genetic variation) in stroke cohorts with outcome data. Cellular study: – study the effect of GWAS-identified SNP on expression and distribution of RYR3 in the endoplasmic reticulum; – study the effect of GWAS-identified SNP on neuronal death and repair induced by reperfusion after ischemic injury in in vitro oxygen-glucose deprivation (OGD) model [Valerio 2009]. Functional study: – study the effect of GWAS-identified SNP on intracellular calcium homeostasis in peripheral blood lymphocytes (PBL) and adipose-derived mesenchymal stromal cells (Ad-MSC) [Viviani 1996].
Western Infirmary General Hospital, Glasgow, Scotland, Acute Stroke Unit, chief Prof. K.R. Lees. Honorary Visiting Research Fellow October – December 2003.
Barrow Neurological Institute, Phoenix, Arizona, Acute Stroke Unit, chief Prof. Robert Spetzler. Clinical Observer – March 2004.
International Award Friends of Milan for Youth – Silver Plate of the President of the Republic and the Lombardy Region Gold Medal awarded for Neurology-Neurobiology in 2009.
RECENT PUBLICATIONS AND CONGRESSES
- Boncoraglio G, Carriero MR, Chiapparini L, Ciceri E, Ciusani E, Erbetta A, Parati EA. Hyperhomocysteinemia and other thrombophilic risk factors in 26 patients with cerebral venous thrombosis. Eur J Neurol. 2004 Jun;11(6):405-9.
- Boncoraglio GB, Bodini A, Brambilla C, Carriero MR, Ciusani E, Parati EA. An effect of the PAI-1 4G/5G polymorphism on cholesterol levels may explain conflicting associations with myocardial infarction and stroke. Cerebrovasc Dis. 2006;22(2-3):191-5.
- Boncoraglio GB, Bersano A, Candelise L, Reynolds BA, Parati EA. Stem cell transplantation for ischemic stroke. Cochrane Database Syst Rev. 2010 Sep 8;(9):CD007231. doi: 10.1002/14651858.CD007231.
- International Stroke Genetics Consortium (ISGC); Wellcome Trust Case Control Consortium 2 (WTCCC2), Bellenguez C, Bevan S, Gschwendtner A, Spencer CC, Burgess AI, Pirinen M, Jackson CA, Traylor M, Strange A, Su Z, Band G, Syme PD, Malik R, Pera J, Norrving B, Lemmens R, Freeman C, Schanz R, James T, Poole D, Murphy L, Segal H, Cortellini L, Cheng YC, Woo D, Nalls MA, Müller-Myhsok B, Meisinger C, Seedorf U, Ross-Adams H, Boonen S, Wloch-Kopec D, Valant V, Slark J, Furie K, Delavaran H, Langford C, Deloukas P, Edkins S, Hunt S, Gray E, Dronov S, Peltonen L, Gretarsdottir S, Thorleifsson G, Thorsteinsdottir U, Stefansson K, Boncoraglio GB, Parati EA, Attia J, Holliday E, Levi C, Franzosi MG, Goel A, Helgadottir A, Blackwell JM, Bramon E, Brown MA, Casas JP, Corvin A, Duncanson A, Jankowski J, Mathew CG, Palmer CN, Plomin R, Rautanen A, Sawcer SJ, Trembath RC, Viswanathan AC, Wood NW, Worrall BB, Kittner SJ, Mitchell BD, Kissela B, Meschia JF, Thijs V, Lindgren A, Macleod MJ, Slowik A, Walters M, Rosand J, Sharma P, Farrall M, Sudlow CL, Rothwell PM, Dichgans M, Donnelly P, Markus HS. Genome-wide association study identifies a variant in HDAC9 associated with large vessel ischemic stroke. Nat Genet. 2012 Feb 5;44(3):328-33. doi: 10.1038/ng.1081.
- Holliday EG, Maguire JM, Evans TJ, Koblar SA, Jannes J, Sturm JW, Hankey GJ, Baker R, Golledge J, Parsons MW, Malik R, McEvoy M, Biros E, Lewis MD, Lincz LF, Peel R, Oldmeadow C, Smith W, Moscato P, Barlera S, Bevan S, Bis JC, Boerwinkle E, Boncoraglio GB, Brott TG, Brown RD Jr, Cheng YC, Cole JW, Cotlarciuc I, Devan WJ, Fornage M, Furie KL, Grétarsdóttir S, Gschwendtner A, Ikram MA, Longstreth WT Jr, Meschia JF, Mitchell BD, Mosley TH, Nalls MA, Parati EA, Psaty BM, Sharma P, Stefansson K, Thorleifsson G, Thorsteinsdottir U, Traylor M, Verhaaren BF, Wiggins KL, Worrall BB, Sudlow C, Rothwell PM, Farrall M, Dichgans M, Rosand J, Markus HS, Scott RJ, Levi C, Attia J; Australian Stroke Genetics Collaborative; International Stroke Genetics Consortium; Wellcome Trust Case Control Consortium 2. Common variants at 6p21.1 are associated with large artery atherosclerotic stroke. Nat Genet. 2012 Oct;44(10):1147-51. doi: 10.1038/ng.2397.
- Traylor M, Farrall M, Holliday EG, Sudlow C, Hopewell JC, Cheng YC, Fornage M, Ikram MA, Malik R, Bevan S, Thorsteinsdottir U, Nalls MA, Longstreth W, Wiggins KL, Yadav S, Parati EA, Destefano AL, Worrall BB, Kittner SJ, Khan MS, Reiner AP, Helgadottir A, Achterberg S, Fernandez-Cadenas I, Abboud S, Schmidt R, Walters M, Chen WM, Ringelstein EB, O’Donnell M, Ho WK, Pera J, Lemmens R, Norrving B, Higgins P, Benn M, Sale M, Kuhlenbäumer G, Doney AS, Vicente AM, Delavaran H, Algra A, Davies G, Oliveira SA, Palmer CN, Deary I, Schmidt H, Pandolfo M, Montaner J, Carty C, de Bakker PI, Kostulas K, Ferro JM, van Zuydam NR, Valdimarsson E, Nordestgaard BG, Lindgren A, Thijs V, Slowik A, Saleheen D, Paré G, Berger K, Thorleifsson G; Australian Stroke Genetics Collaborative, Wellcome Trust Case Control Consortium 2 (WTCCC2), Hofman A, Mosley TH, Mitchell BD, Furie K, Clarke R, Levi C, Seshadri S, Gschwendtner A, Boncoraglio GB, Sharma P, Bis JC, Gretarsdottir S, Psaty BM, Rothwell PM, Rosand J, Meschia JF, Stefansson K, Dichgans M, Markus HS; International Stroke Genetics Consortium. Genetic risk factors for ischaemic stroke and its subtypes (the METASTROKE collaboration): a meta-analysis of genome-wide association studies. Lancet Neurol. 2012 Nov;11(11):951-62. doi: 10.1016/S1474-4422(12)70234-X. Epub 2012 Oct 5. Erratum in: Lancet Neurol. 2015 Aug;14(8):788.
- Boncoraglio GB, Piazza F, Savoiardo M, Farina L, DiFrancesco JC, Prioni S, Tagliavini F, Parati EA, Giaccone G. Prodromal Alzheimer’s disease presenting as cerebral amyloid angiopathy-related inflammation with spontaneous amyloid-related imaging abnormalities and high cerebrospinal fluid anti-Aβ autoantibodies. J Alzheimers Dis. 2015;45(2):363-7. doi: 10.3233/JAD-142376.
- NINDS Stroke Genetics Network (SiGN); International Stroke Genetics Consortium (ISGC). Loci associated with ischaemic stroke and its subtypes (SiGN): a genome-wide association study. Lancet Neurol. 2016 Feb;15(2):174-184. doi: 10.1016/S1474-4422(15)00338-5.
- Neurology Working Group of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium, the Stroke Genetics Network (SiGN), and the International Stroke Genetics Consortium (ISGC). Identification of additional risk loci for stroke and small vessel disease: a meta-analysis of genome-wide association studies. Lancet Neurol. 2016 Jun;15(7):695-707. doi: 10.1016/S1474-4422(16)00102-2.
- Traylor M, Rutten-Jacobs LC, Thijs V, Holliday EG, Levi C, Bevan S, Malik R, Boncoraglio G, Sudlow C, Rothwell PM, Dichgans M, Markus HS. Genetic Associations With White Matter Hyperintensities Confer Risk of Lacunar Stroke. Stroke. 2016 May;47(5):1174-9. doi: 10.1161/STROKEAHA.115.011625.