Hope Center Member Publications: September 24, 2023

Defining the causes of sporadic Parkinson’s disease in the global Parkinson’s genetics program (GP2)
(2023) npj Parkinson’s Disease, 9 (1), art. no. 131, . 

Towns, C.^a , Richer, M.^a , Jasaityte, S.^a , Stafford, E.J.^a b , Joubert, J.^a , Antar, T.^c , Martinez-Carrasco, A.^a b , Makarious, M.B.^a c d , Casey, B.^e f , Vitale, D.^d g h , Levine, K.^g h , Leonard, H.^c g h i , Pantazis, C.B.^d g , Screven, L.A.^g , Hernandez, D.G.^c , Wegel, C.E.^j , Solle, J.^e , Nalls, M.A.^c d g h , Blauwendraat, C.^d g k , Singleton, A.B.^c g l , Tan, M.M.X.^m , Iwaki, H.^c g h , Morris, H.R.^a b , Gatto, E.M.ⁿ , Kauffman, M.^o , Khachatryan, S.^p , Tavadyan, Z.^p , Shepherd, C.E.^q , Hunter, J.^r , Kumar, K.^s , Ellis, M.^t , Rentería, M.E.^u , Koks, S.^v , Zimprich, A.^w , Schumacher-Schuh, A.F.^x , Rieder, C.^y , Awad, P.S.^z , Tumas, V.^aa , Camargos, S.^ab , Fon, E.A.^ac , Monchi, O.^ad , Fon, T.^ae , Galleguillos, B.P.^af , Miranda, M.^ag , Bustamante, M.L.^ah , Olguin, P.^af , Chana, P.^ai , Tang, B.^aj , Shang, H.^ak , Guo, J.^al , Chan, P.^am , Luo, W.^an , Arboleda, G.^ao , Orozco, J.^ap , del Rio, M.J.^aq , Hernandez, A.^ar , Salama, M.^as , Kamel, W.A.^at , Zewde, Y.Z.^au , Brice, A.^av , Corvol, J.-C.^aw , Westenberger, A.^ax , Illarionova, A.^ay , Mollenhauer, B.^az , Klein, C.^ax , Vollstedt, E.-J.^ax , Hopfner, F.^ba , Höglinger, G.^ba , Madoev, H.^ax , Trinh, J.^ax , Junker, J.^ax , Lohmann, K.^ax , Lange, L.M.^bb , Sharma, M.^bc , Groppa, S.^bd , Gasser, T.^bc , Fang, Z.-H.^be , Akpalu, A.^bf , Xiromerisiou, G.^bg , Hadjigorgiou, G.^bg , Dagklis, I.^bh , Tarnanas, I.^bi , Stefanis, L.^bj , Stamelou, M.^bk , Dadiotis, E.^bg , Medina, A.^bl , Chan, G.H.-F.^bm , Ip, N.^bn , Cheung, N.Y.-F.^bm , Chan, P.^bn , Zhou, X.^bn , Kishore, A.^bo , Kp, D.^bp , Pal, P.^bq , Kukkle, P.L.^br , Rajan, R.^bs , Borgohain, R.^bt , Salari, M.^bu , Quattrone, A.^bv , Valente, E.M.^bw , Parnetti, L.^bx , Avenali, M.^bw , Schirinzi, T.^by , Funayama, M.^bz , Hattori, N.^ca , Shiraishi, T.^cb , Karimova, A.^cc , Kaishibayeva, G.^cc , Shambetova, C.^cd , Krüger, R.^ce , Tan, A.H.^cf , Ahmad-Annuar, A.^cf , Norlinah, M.I.^cg , Murad, N.A.A.^ch , Azmin, S.^ci , Lim, S.-Y.^cf , Mohamed, W.^cj , Tay, Y.W.^cf , Martinez-Ramirez, D.^ck , Rodriguez-Violante, M.^cl , Reyes-Pérez, P.^cm , Tserensodnom, B.^cn , Ojha, R.^co , Anderson, T.J.^cp , Pitcher, T.L.^cp , Sanyaolu, A.^cq , Okubadejo, N.^cq , Ojo, O.^cr , Aasly, J.O.^cs , Pihlstrøm, L.^ct , Tan, M.^ct , Ur-Rehman, S.^cu , Cornejo-Olivas, M.^cv , Doquenia, M.L.^cw , Rosales, R.^cw , Vinuela, A.^cx , Iakovenko, E.^cy , Mubarak, B.A.^cz , Umair, M.^da , Tan, E.-K.^db , Foo, J.N.^dc , Amod, F.^dd , Carr, J.^de , Bardien, S.^df , Jeon, B.^dg , Kim, Y.J.^dh , Cubo, E.^di , Alvarez, I.^dj , Hoenicka, J.^dk , Beyer, K.^dl , Periñan, M.T.^dm , Pastor, P.^dn , El-Sadig, S.^do , Zweier, C.^dp , Krack, P.^dp , Lin, C.-H.^dq , Wu, H.-C.^dr , Kung, P.-J.^ds , Wu, R.-M.^dq , Wu, Y.^dr , Amouri, R.^dt , Sassi, S.B.^du , Başak, A.N.^dv , Genc, G.^dw , Çakmak, Ö.Ö.^dv , Ertan, S.^dv , Noyce, A.^dx , Schrag, A.^b , Schapira, A.^b , Carroll, C.^dy , Bale, C.^dz , Grosset, D.^ea , Houlden, H.^b , Hardy, J.^b , Mok, K.Y.^b , Rizig, M.^b , Wood, N.^b , Williams, N.^eb , Okunoye, O.^b , Lewis, P.A.^ec , Kaiyrzhanov, R.^b , Weil, R.^b , Love, S.^ed , Stott, S.^ee , Jasaitye, S.^b , Dey, S.^dx , Obese, V.^b , Espay, A.^ef , O’Grady, A.^f , Sobering, A.K.^eg , Siddiqi, B.^f , Fiske, B.^f , Jonas, C.^eh , Cruchaga, C.^ei , Comart, C.^f , Wegel, C.^ej , Hall, D.^ek , Hernandez, D.^d , Shiamim, E.^el , Riley, E.^em , Faghri, F.^d , Serrano, G.E.^en , Chen, H.^eo , Mata, I.F.^ep , Sarmiento, I.J.K.^eq , Williamson, J.^el , Kim, J.J.^d , Jankovic, J.^er , Shulman, J.^es , Solle, J.C.^f , Murphy, K.^f , Nuytemans, K.^et , Kieburtz, K.^eu , Markopoulou, K.^ev , Marek, K.^ew , Levine, K.S.^h , Chahine, L.M.^ex , Ibanez, L.^ei , Screven, L.^l , Ruffrage, L.^ey , Shulman, L.^ez , Marsili, L.^ef , Kuhl, M.^f , Dean, M.^ey , Koretsky, M.^d , Puckelwartz, M.J.^fa , Inca-Martinez, M.^ep , Louie, N.^f , Mencacci, N.E.^eq , Albin, R.^fb , Alcalay, R.^fc , Walker, R.^fd , Bandres-Ciga, S.^d , Chowdhury, S.^f , Dumanis, S.^fe , Lubbe, S.^fa , Xie, T.^ff , Foroud, T.^fg , Beach, T.^fh , Sherer, T.^f , Song, Y.^d , Nguyen, D.^fi , Nguyen, T.^fi , Atadzhanov, M.^fj

^a Department of Clinical and Movement Neurosciences, Queen Square Institute of Neurology, University College London, London, United Kingdom
^b University College London, London, United Kingdom
^c Molecular Genetics Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, United States
^d National Institutes of Health, Bethesda, MD, United States
^e Department of Clinical Research, Michael J. Fox Foundation for Parkinson’s Research, New York City, NY, United States
^f The Michael J. Fox Foundation for Parkinson’s Research, New York, NY, United States
^g Center for Alzheimer’s and Related Dementias (CARD), National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, United States
^h Data Tecnica International, Washington, DC, United States
ⁱ National Institute on Aging/National Institutes of Health, Bethesda, MD, United States
^j Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, United States
^k Integrative Genomics Unit, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, United States
^l National Institute on Aging, Bethesda, MD, United States
^m Department of Neurology, Oslo University Hospital, Oslo, Norway
ⁿ Sanatorio de la Trinidad Mitre- INEBA, Buenos Aires, Argentina
^o Hospital JM Ramos Mejia, Buenos Aires, Argentina
^p Somnus Neurology Clinic, Yerevan, Armenia
^q Neuroscience Research Australia, Sydney, NSW, Australia
^r ANZAC Research Institute, Concord, NSW, Australia
^s Garvan Institute of Medical Research and Concord Repatriation General Hospital, Darlinghurst, NSW, Australia
^t Concord Hospital, Concord, NSW, Australia
^u QIMR Berghofer Medical Research Institute, Herston, QLD, Australia
^v Murdoch University, Perth, Australia
^w Medical University Vienna Austria, Vienna, Austria
^x Universidade Federal do Rio Grande do Sul / Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil
^y Federal University of Health Sciences of Porto Alegre, Porto Alegre, Brazil
^z Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
^aa University of São Paulo, São Paulo, Brazil
^ab Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
^ac Montreal Neurological Institute, Montreal, QC, Canada
^ad Institut universitaire de gériatrie de Montréal, Montreal, QC, Canada
^ae McGill University, Montreal, QC, Canada
^af Universidad de Chile, Santiago, Chile
^ag Fundación Diagnosis, Santiago, Chile
^ah Faculty of Medicine Universidad de Chile, Santiago, Chile
^ai CETRAM, Santiago, Chile
^aj Central South University, Changsha, China
^ak West China Hospital Sichuan University, Chengdu, China
^al Xiangya Hospital, Changsha, China
^am Capital Medical University, Beijing, China
^an Zhejiang University, Hangzhou, China
^ao Universidad Nacional de Colombia, Bogotá, Colombia
^ap Fundación Valle del Lili, Santiago De Cali, Colombia
^aq University of Antioquia, Medellin, Colombia
^ar University of Costa Rica, San Jose, Costa Rica
^as The American University in Cairo, Cairo, Egypt
^at Beni-Suef University, Beni Suef, Egypt
^au Addis Ababa University, Addis Ababa, Ethiopia
^av Paris Brain Institute, Paris, France
^aw Sorbonne Université, Paris, France
^ax University of Lübeck, Lübeck, Germany
^ay Deutsches Zentrum für Neurodegenerative Erkrankungen, Göttingen, Germany
^az University Medical Center Göttingen, Göttingen, Germany
^ba Department of Neurology, University Hospital, LMU Munich, Munich, Germany
^bb University of Lübeck and University Medical Center Schleswig-Holstein, Lübeck, Germany
^bc University of Tubingen, Tübingen, Germany
^bd University of Mainz, Mainz, Germany
^be The German Center for Neurodegenerative Diseases, Göttingen, Germany
^bf University of Ghana Medical School, Accra, Ghana
^bg University of Thessaly, Volos, Greece
^bh Aristotle University of Thessaloniki, Thessaloniki, Greece
^bi Ionian University, Corfu, Greece
^bj Biomedical research Foundation of the Academy of Athens, Athens, Greece
^bk Diagnostic and Therapeutic Centre HYGEIA Hospital, Marousi, Greece
^bl Hospital San Felipe, Tegucigalpa, Honduras
^bm Queen Elizabeth Hospital, Kowloon, Hong Kong
^bn The Hong Kong University of Science and Technology, Kowloon, Hong Kong
^bo Aster Medcity, Kochi, India
^bp Sree Chitra Tirunal Institute for Medical Sciences and Technology, Thiruvananthapuram, India
^bq National Institute of Mental Health & Neurosciences, Bengaluru, India
^br Manipal Hospital, Delhi, India
^bs All India Institute of Medical Sciences, Delhi, India
^bt Nizam’s Institute Of Medical Sciences, Hyderabad, India
^bu Shahid Beheshti University of Medical Science, Tehran, Iran
^bv Magna Græcia University of Catanzaro, Catanzaro, Italy
^bw University of Pavia, Pavia, Italy
^bx University of Perugia, Perugia, Italy
^by University of Rome Tor Vergata, Rome, Italy
^bz Juntendo University, Tokyo, Japan
^ca Juntendo University faculty of medicine, Tokyo, Japan
^cb Jikei University School of Medicine, Tokyo, Japan
^cc Institute of Neurology and Neurorehabilitation, Almaty, Kazakhstan
^cd Kyrgyz State Medical Academy, Bishkek, Kyrgyzstan
^ce University of Luxembourg, Luxembourg, Luxembourg
^cf University of Malaya, Kuala Lumpur, Malaysia
^cg Universiti Kebangsaan Malaysia, Selangor, Malaysia
^ch UKM Medical Molecular Biology Institute, Kuala Lumpur, Malaysia
^ci Universiti Kebangsaan Malaysia Medical Centre, Kuala Lumpur, Malaysia
^cj International Islamic University, Kuala Lumpur, Malaysia
^ck Tecnologico de Monterrey, Monterrey, Mexico
^cl Instituto Nacional de Neurologia y Neurocirugia, Mexico City, Mexico
^cm Universidad Nacional Autónoma de México, Mexico City, Mexico
^cn Mongolian National University of Medical Sciences, Ulaanbaatar, Mongolia
^co Tribhuvan University, Kirtipur, Nepal
^cp University of Otago, Dunedin, New Zealand
^cq University of Lagos, Lagos, Nigeria
^cr College of Medicine of the University of Lagos, Lagos, Nigeria
^cs Norwegian University of Science and Technology, Trondheim, Norway
^ct Oslo University Hospital, Oslo, Norway
^cu University of Science and Technology Bannu, Bannu, Pakistan
^cv Universidad Cientifica del Sur, Lima, Peru
^cw Metropolitan Medical Center, Manila, Philippines
^cx University of Puerto Rico, San Juan, Puerto Rico
^cy Research Center of Neurology, Moscow, Russian Federation
^cz King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
^da King Abdullah International Medical Research Center, Jeddah, Saudi Arabia
^db National Neuroscience Institute, Singapore, Singapore
^dc Nanyang Technological University, Singapore, Singapore
^dd University of KwaZulu-Natal, Durban, South Africa
^de University of Stellenbosch, Stellenbosch, South Africa
^df Stellenbosch University, Stellenbosch, South Africa
^dg Seoul National University Hospital, Seoul, South Korea
^dh Yongin Severance Hospital, Seoul, South Korea
^di Hospital Universitario Burgos, Burgos, Spain
^dj University Hospital Mutua Terrassa, Barcelona, Spain
^dk Institut de Recerca Sant Joan de Deu, Barcelona, Spain
^dl Research Institute Germans Trias i Pujol, Barcelona, Spain
^dm Instituto de Biomedicina de Sevilla, Seville, Spain
^dn University Hospital Germans Trias i Pujol, Barcelona, Spain
^do Faculty of medicine university of Khartoum, Khartoum, Sudan
^dp Inselspital Bern, University of Bern, Bern, Switzerland
^dq National Taiwan University Hospital, Taipei City, Taiwan
^dr Chang Gung Memorial Hospital, Taoyuan City, Taiwan
^ds National Taiwan University, Taipei City, Taiwan
^dt National Institute Mongi Ben Hamida of Neurology, Tunis, Tunisia
^du Mongi Ben Hmida National Institute of Neurology, Tunis, Tunisia
^dv Koç University, Istanbul, Turkey
^dw Sisli Etfal Training and Research Hospital, Istanbul, Turkey
^dx Queen Mary University of London, London, United Kingdom
^dy University of Plymouth, Plymouth, United Kingdom
^dz Parkinson’s UK, London, United Kingdom
^ea University of Glasgow, Glasgow, United Kingdom
^eb Cardiff University, Cardiff, United Kingdom
^ec Royal Veterinary College University of London, London, United Kingdom
^ed University of Bristol, Bristol, United Kingdom
^ee Cure Parkinson’s, London, United Kingdom
^ef University of Cincinnati, Cincinnati, OH, United States
^eg Augusta University / University of Georgia Medical Partnership, Augusta, GA, United States
^eh Mid-Atlantic Permanente Medical Group, Bethesda, MD, United States
^ei Washington University, St. Louis, MO, United States
^ej Indiana University, Bloomington, IN, United States
^ek Rush University, Chicago, IL, United States
^el Kaiser Permanente, Oakland, CA, United States
^em Coalition for Aligning Science, Washington, WA, United States
^en Banner Sun Health Research Institute, Sun City, AZ, United States
^eo Michigan State University, East Lansing, MI, United States
^ep Cleveland Clinic, Cleveland, OH, United States
^eq Northwestern University, Evanston, IL, United States
^er Baylor College of Medicine, Houston, TX, United States
^es Baylor College of Medicine, Texas Children’s Hospital, Houston, TX, United States
^et University of Miami Miller School of Medicine, Miami, FL, United States
^eu Beth Israel Deaconess Medical Center, Boston, MA, United States
^ev North Shore University Health System, Chicago, IL, United States
^ew Institute for Neurodegenerative Disorders, New Haven, CT, United States
^ex University of Pittsburgh, Pittsburgh, PA, United States
^ey University of Alabama at Birmingham, Birmingham, AL, United States
^ez University of Maryland, Baltimore, MD, United States
^fa Northwestern University, Chicago, IL, United States
^fb Universit of Michigan, Ann Arbor, MI, United States
^fc Columbia University, New York, NY, United States
^fd James J. Peters Veterans Affairs Medical Center, New York, NY, United States
^fe Aligning Science Across Parkinson’s, Washington, WA, United States
^ff University of Chicago, Chicago, IL, United States
^fg Indiana University School of Medicine, Indianapolis, IN, United States
^fh Sun Health Research Institution, Sun City, AZ, United States
^fi Hue University, Huế, Viet Nam
^fj University of Zambia, Lusaka, Zambia

Abstract
The Global Parkinson’s Genetics Program (GP2) will genotype over 150,000 participants from around the world, and integrate genetic and clinical data for use in large-scale analyses to dramatically expand our understanding of the genetic architecture of PD. This report details the workflow for cohort integration into the complex arm of GP2, and together with our outline of the monogenic hub in a companion paper, provides a generalizable blueprint for establishing large scale collaborative research consortia. © 2023, Springer Nature Limited.

Funding details
National Institutes of HealthNIH
U.S. Department of Health and Human ServicesHHSZO1 AG000949
National Institute on AgingNIA
Michael J. Fox Foundation for Parkinson’s ResearchMJFF
International Parkinson and Movement Disorder SocietyMDS
Wellcome TrustWT
PSP AssociationPSPA
Aligning Science Across Parkinson’sASAP
PCB Solutions
Medical Research CouncilMRC
Drake Foundation

Document Type: Article
Publication Stage: Final
Source: Scopus

A Novel Brain PET Radiotracer for Imaging Alpha Synuclein Fibrils in Multiple System Atrophy
(2023) Journal of Medicinal Chemistry, . 

Kim, H.Y.^a , Chia, W.K.^a , Hsieh, C.-J.^a , Saturnino Guarino, D.^a , Graham, T.J.A.^a , Lengyel-Zhand, Z.^a , Schneider, M.^a , Tomita, C.^a , Lougee, M.G.^b , Kim, H.J.^c , Pagar, V.V.^b , Lee, H.^a , Hou, C.^a , Garcia, B.A.^c , Petersson, E.J.^b , O’Shea, J.^d , Kotzbauer, P.T.^d , Mathis, C.A.^e , Lee, V.M.^f , Luk, K.C.^f , Mach, R.H.^a

^a Department of Radiology, Perelman School of Medicine, University of Pennsylvania, 231 S. 34th Street, Philadelphia, PA 19104-6323, United States
^b Department of Chemistry, University of Pennsylvania, Pennsylvania, Philadelphia, 19104-6323, United States
^c Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Pennsylvania, Philadelphia, 19104-6303, United States
^d Department of Neurology, Washington University School of Medicine, Saint Louis, MO 63110-1010, United States
^e Department of Radiology, University of Pittsburgh, Pittsburgh, PA 15213, United States
^f Center for Neurodegenerative Disease Research, Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104-2676, United States

Abstract
Abnormal α-synuclein (α-syn) aggregation characterizes α-synucleinopathies, including Parkinson’s disease (PD) and multiple system atrophy (MSA). However, no suitable positron emission tomography (PET) radiotracer for imaging α-syn in PD and MSA exists currently. Our structure-activity relationship studies identified 4-methoxy-N-(4-(3-(pyridin-2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)phenyl)benzamide (4i) as a PET radiotracer candidate for imaging α-syn. In vitro assays revealed high binding of 4i to recombinant α-syn fibrils (inhibition constant (Ki) = 6.1 nM) and low affinity for amyloid beta (Aβ) fibrils in Alzheimer’s disease (AD) homogenates. However, [3H]4i also exhibited high specific binding to AD, progressive supranuclear palsy, and corticobasal degeneration tissues as well as PD and MSA tissues, suggesting notable affinity to tau. Nevertheless, the specific binding to pathologic α-syn aggregates in MSA post-mortem brain tissues was significantly higher than in PD tissues. This finding demonstrated the potential use of [11C]4i as a PET tracer for imaging α-syn in MSA patients. Nonhuman primate PET studies confirmed good brain uptake and rapid washout for [11C]4i. © 2023 American Chemical Society.

Funding details
P01AG019724, P30AG062422, U01AG057195, U19AG063911
National Institutes of HealthNIHNS072026, T32-AG000255
Michael J. Fox Foundation for Parkinson’s ResearchMJFF
Rainwater Charitable FoundationRCF

Document Type: Article
Publication Stage: Article in Press
Source: Scopus

Human microglia maturation is underpinned by specific gene regulatory networks. Immunity. 2023 Sep 12;56(9):2152-2171.e13.

Han CZ, Li RZ, Hansen E, Trescott S, Fixsen BR, Nguyen CT, Mora CM, Spann NJ, Bennett HR, Poirion O, Buchanan J, Warden AS, Xia B, Schlachetzki JCM, Pasillas MP, Preissl S, Wang A, O’Connor C, Shriram S, Kim R, Schafer D, Ramirez G, Challacombe J, Anavim SA, Johnson A, Gupta M, Glass IA, Levy ML, Haim SB, Gonda DD, Laurent L, Hughes JF, Page DC, Blurton-Jones M, Glass CK, Coufal NG.

Abstract
Microglia phenotypes are highly regulated by the brain environment, but the transcriptional networks that specify the maturation of human microglia are poorly understood. Here, we characterized stage-specific transcriptomes and epigenetic landscapes of fetal and postnatal human microglia and acquired corresponding data in induced pluripotent stem cell (iPSC)-derived microglia, in cerebral organoids, and following engraftment into humanized mice. Parallel development of computational approaches that considered transcription factor (TF) co-occurrence and enhancer activity allowed prediction of shared and state-specific gene regulatory networks associated with fetal and postnatal microglia. Additionally, many features of the human fetal-to-postnatal transition were recapitulated in a time-dependent manner following the engraftment of iPSC cells into humanized mice. These data and accompanying computational approaches will facilitate further efforts to elucidate mechanisms by which human microglia acquire stage- and disease-specific phenotypes. © 2023 The Authors

Author keywords
epigenomics; humanized; microglia; neurodevelopment; neurological disorders; stem cells; transcription factors; transcriptomics