PEOPLE

Naiara Aquizu Lopez, PhD

Assistant Professor of Pathology and Laboratory Medicine
Perelman School of Medicine at the University of Pennsylvania 

Contact InformationThe Children's Hospital of Philadelphia
3501 Civic Center Boulevard
5052 Colket Translational Research Building

Philadelphia, PA, 19104
Office: 215-590-2232
Fax: 215-590-3660

Email: aquizun@email.chop.edu

Itmat Expertise

The goal of the Akizu Lab is to uncover genetic and epigenetic mechanisms of developmental brain disorders and advance diagnostic and treatment strategies. To achieve our goals, we integrate human genetic discoveries with functional studies performed in human pluripotent stem cells and animal models using cutting edge technologies. Our research has revealed novel genetic causes of developmental brain disorders, elucidated mechanisms that provide vulnerability to neurodegeneration in children, and generated innovative model systems for functional studies.

Research Expertise

While the number of genetic variants associated with developmental brain disorders has exponentially increased, the pathogenic effect for most of them remains unknown, hindering progress in diagnosis and treatment. At Akizu Lab we integrate human genetics with functional studies performed in human pluripotent stem cells (hPSC) and animal models to transform genetic discoveries into novel insights on how genetic variants induce pathology. Our findings enhance the care and management of individuals affected by brain disorders, reveal genetic and epigenetic mechanisms underlaying human brain development and uncover factors that provide selective vulnerability to developing neurons. Our current projects are focused in four lines of research:

1-Uncovering the causes of neurodevelopmental disorders, including autism and intellectual disabilities. Through collaborations with clinical geneticists worldwide, our lab is at the forefront of identifying genetic causes that inform novel diagnoses and treatments for neurodevelopmental disorders (Gracia-Diaz et al., Nat Commun 2023; Li et al., J Clin Invest 2024). Although these disorders are highly heritable, the underlying causes are often complex and include gene and environment interactions that we continuously survey in the lab (Saade et al., Cell Stem Cell 2020).

2-Revealing chromatin-mediated epigenetic mechanisms that lead to neuronal diversity generation in the human brain. Variants in genes encoding chromatin regulators are recurrently associated with neurodevelopmental disorders. Focusing on the Polycomb Repressive Complex 2, a chromatin regulatory complex involved in the epigenetic transmission of cellular identity, our work aims to uncover how diverse chromatin machineries cooperate to determine neuronal subtypes during brain development and how their disruption causes disease (Akizu et al., Development 2010; Akizu et al., Open Biology 2016; Gracia-Diaz et al., Nat Commun 2023).

3-Elucidating mechanisms that confer selective vulnerability to neurodegeneration in developmental brain disorders. The developing human brain is exquisitely sensitive to metabolic dysregulation. Founded on two childhood neurodegenerative disorders of the posterior brain that we genetically defined (Akizu et al., Cell 2013; Akizu et al., Nat Genet 2015), our work aims to unlock how metabolic enzyme polymerization protects neurons from degeneration (Flores et al., BioRxiv 2024) and why the cerebellum is selectively vulnerable to lipid and lysosome homeostatic defects (Zhou and Sanchez et al., JCI Insights 2024).

4-Discovering treatments for neurodevelopmental disorders. Despite evidence demonstrating that neurodevelopmental disorders are treatable, successful treatments are still scarce. Leveraging our mechanistic studies, we aim to develop innovative strategies to treat these disorders. In collaboration with the GoldbergNeurolab at the Children’s Hospital of Philadelphia, we contributed to their efforts in unraveling a targeted therapy that improves seizures and motor behavioral defects in a mouse model of Progressive Myoclonus Epilepsy (Feng et al., Cell Rep Med. 2024). We are also developing novel epigenetic treatments for neurodevelopmental disorders.


CURRENT LAB MEMBERS
Thomas Roule, Ph.D., Postdoctoral Fellow roulet@chop.edu
Vanessa B. Sanchez, Neuroscience graduate group student, vssnchez@pennmedicine.upenn.edu
Lilly Ryll, Neuroscience graduate group student, Lilly.Ryll@Pennmedicine.upenn.edu
Jasmine Akoto, Genetic and Epigenetic graduate group student, Jasmine.Akoto@Pennmedicine.upenn.edu
James Bauer, Neuroscience graduate group student, James.Bauer@Pennmedicine.upenn.edu
Teresa Jimenez, Lab Manager, jimenezsat@chop.edu
Stephanie Gagnon, Stem Cell Technician, gagnons@chop.edu

Education

BS (Biology), University Pompeu Fabra, Barcelona, 2005
PhD (Biomedicine), University of Barcelona, 2010

Specialty Certification

Postgraduate Training

Graduate Student; Epigenetics, Molecular Biology Institute of Barcelona, Spanish National Research Council, Department of Molecular Genomics, 2005-2010
Postdoctoral Fellow; Neurogenetics, University of California, San Diego, Department of Neurosciences, 2010-2014
Postdoctoral Fellow; Neural Development, The Scripps Research Institute, Department of Molecular and Cellular Neurosciences;, 2014-2016

Awards and Honors

Maximum Honor Prize, University Pompeu Fabra, Barcelona, Spain, 2005
Predoctoral Fellowship from Spanish National Research Council (I3P), 2006-2010
Summa cum laude in distinction of Doctoral Thesis, University of Barcelona, Spain, 2010
Postdoctoral Training Grant, California Institute of Regenerative Medicine, 2011-2013
K99/R00 NIH Pathway to Independence Award, The Scripps Research Institute, 2014-2017

Memberships and Professional Organizations

Grant review for Medical Research Council (MRC), UK., 2017 - 2017
Neurogenesis and Cell Fate Study Section, National Institute of Health (NIH), 2022 - 2022
ZRG1 BN-V Study Section, National Institute of Health (NIH), 2023 - 2023
ZRG1 BN-G Study Section, National Institute of Health (NIH), 2024 - 2024

Web Links


Selected Publications

IMPDH2 filaments protect from neurodegeneration in AMPD2 deficiency.

Flores-Mendez M, Ohl L, Roule T, Zhou Y, Tintos-Hernández JA, Walsh K, Ortiz-González XR, Akizu N., EMBO Rep., 2024, PMID:38328116

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Altered lipid homeostasis is associated with cerebellar neurodegeneration in SNX14 deficiency.

Zhou Y, Sanchez VB, Xu P, Roule T, Flores-Mendez M, Ciesielski B, Yoo D, Teshome H, Jimenez T, Liu S, Henne M, O'Brien T, He Y, Mesaros C, Akizu N., JCI Insight., 2024, PMID:38625743

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KOLF2.1J iPSCs carry CNVs linked to neurodevelopmental disorders.

Gracia-Diaz C, Perdomo JE, Khan ME, Disanza B, Cajka GG, Lei S, Gagne A, Maguire JA, Roule T, Shalem O, Bhoj EJ, Ahrens-Nicklas RC, French D, Goldberg EM, Wang K, Glessner J, Akizu N., Cell Stem Cell., 2024

Spliceosome malfunction causes neurodevelopmental disorders with overlapping features.

Li D, Wang Q, Bayat A, Battig MR, Zhou Y, Bosch DG, van Haaften G, Granger L, Petersen AK, Pérez-Jurado LA, Aznar-Laín G, Aneja A, Hancarova M, Bendova S, Schwarz M, Kremlikova Pourova R, Sedlacek Z, Keena BA, March ME, Hou C, O'Connor N, Bhoj EJ, Harr MH, Lemire G, Boycott KM, Towne M, Li M, Tarnopolsky M, Brady L, Parker MJ, Faghfoury H, Parsley LK, Agolini E, Dentici ML, Novelli A, Wright M, Palmquist R, Lai K, Scala M, Striano P, Iacomino M, Zara F, Cooper A, Maarup TJ, Byler M, Lebel RR, Balci TB, Louie R, Lyons M, Douglas J, Nowak C, Afenjar A, Hoyer J, Keren B, Maas SM, Motazacker MM, Martinez-Agosto JA, Rabani AM, McCormick EM, Falk MJ, Ruggiero SM, Helbig I, Møller RS, Tessarollo L, Tomassoni Ardori F, Palko ME, Hsieh TC, Krawitz PM, Ganapathi M, Gelb BD, Jobanputra V, Wilson A, Greally J, Jacquemont S, Jizi K, Bruel AL, Quelin C, Misra VK, Chick E, Romano C, Greco D, Arena A, Morleo M, Nigro V, Seyama R, Uchiyama Y, Matsumoto N, Taira R, Tashiro K, Sakai Y, Yigit G, Wollnik B, Wagner M, Kutsche B, Hurst AC, Thompson ML, Schmidt R, Randolph L, Spillmann RC, Shashi V, Higginbotham EJ, Cordeiro D, Carnevale A, Costain G, Khan T, Funalot B, Tran Mau-Them F, Fernandez Garcia Moya L, Garcia-Minaur S, Osmond M, Chad L, Quercia N, Carrasco D, Li C, Sanchez-Valle A, Kelley M, Nizon M, Jensson BO, Sulem P, Stefansson K, Gorokhova S, Busa T, Rio M, Hadj Habdallah H, Lesieur-Sebellin M, Amiel J, Pingault V, Mercier S, Vincent M, Philippe C, Fatus-Fauconnier C, Friend K, Halligan RK, Biswas S, Rosser J, Shoubridge C, Corbett M, Barnett C, Gecz J, Leppig K, Slavotinek A, Marcelis C, Pfundt R, de Vries BB, van Slegtenhorst MA, Brooks AS, Cogne B, Rambaud T, Tumer Z, Zackai EH, Akizu N, Song Y and Hakonarson H., J Clin Invest., 2024, PMID:37962958

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Targeted therapy improves cellular dysfunction, ataxia, and seizure susceptibility in a model of a progressive myoclonus epilepsy.

Feng H, Clatot J, Kaneko K, Flores-Mendez M, Wengert ER, Koutcher C, Hoddeson E, Lopez E, Lee D, Arias L, Liang Q, Zhang X, Somarowthu A, Covarrubias M, Gunthorpe MJ, Large CH, Akizu N, Goldberg EM., Cell Rep Med., 2024, PMID:38266642

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Gain and loss of function variants in EZH1 disrupt neurogenesis and cause dominant and recessive neurodevelopmental disorders.

Gracia-Diaz C, Zhou Y, Yang Q, Maroofian R, Espana-Bonilla P, Lee CH, Zhang S, Padilla N, Fueyo R, Waxman EA, Lei S, Otrimski G, Li D, Sheppard SE, Mark P, Harr MH, Hakonarson H, Rodan L, Jackson A, Vasudevan P, Powel C, Mohammed S, Maddirevula S, Alzaidan H, Faqeih EA, Efthymiou S, Turchetti V, Rahman F, Maqbool S, Salpietro V, Ibrahim SH, di Rosa G, Houlden H, Alharbi MN, Al-Sannaa NA, Bauer P, Zifarelli G, Estaras C, Hurst ACE, Thompson ML, Chassevent A, Smith-Hicks CL, de la Cruz X, Holtz AM, Elloumi HZ, Hajianpour MJ, Rieubland C, Braun D, Banka S; Genomic England Research Consortium; French DL, Heller EA, Saade M, Song H, Ming GL, Alkuraya FS, Agrawal PB, Reinberg D, Bhoj EJ, Martínez-Balbás MA, Akizu N., Nat Commun. 14(): 4109, 2023, PMID:37433783

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Mechanism of KMT5B haploinsufficiency in neurodevelopment in humans and mice.

Sheppard SE, Bryant L, Wickramasekara RN, Vaccaro C, Robertson B, Hallgren J, Hulen J, Watson CJ, Faundes V, Duffourd Y, Lee P, Simon MC, de la Cruz X, Padilla N, Flores-Mendez M, Akizu N, Smiler J, Pellegrino Da Silva R, Li D, March M, Diaz-Rosado A, Peixoto de Barcelos I, Choa ZX, Lim CY, Dubourg C, Journel H, Demurger F, Mulhern M, Akman C, Lippa N, Andrews M, Baldridge D, Constantino J, van Haeringen A, Snoeck-Streef I, Chow P, Hing A, Graham JM Jr, Au M, Faivre L, Shen W, Mao R, Palumbos J, Viskochil D, Gahl W, Tifft C, Macnamara E, Hauser N, Miller R, Maffeo J, Afenjar A, Doummar D, Keren B, Arn P, Macklin-Mantia S, Meerschaut I, Callewaert B, Reis A, Zweier C, Brewer C, Saggar A, Smeland MF, Kumar A, Elmslie F, Deshpande C, Nizon M, Cogne B, van Ierland Y, Wilke M, van Slegtenhorst M, Koudijs S, Chen JY, Dredge D, Pier D, Wortmann S, Kamsteeg EJ, Koch J, Haynes D, Pollack L, Titheradge H, Ranguin K, Denommé-Pichon AS, Weber S, Pérez de la Fuente R, Sánchez Del Pozo J, Lezana Rosales JM, Joset P, Steindl K, Rauch A, Mei D, Mari F, Guerrini R, Lespinasse J, Tran Mau-Them F, Philippe C, Dauriat B, Raymond L, Moutton S, Cueto-González AM, Tan TY, Mignot C, Grotto S, Renaldo F, Drivas TG, Hennessy L, Raper A, Parenti I, Kaiser FJ, Kuechler A, Busk ØL, Islam L, Siedlik JA, Henderson LB, Juusola J, Person R, Schnur RE, Vitobello A, Banka S, Bhoj EJ, Stessman HAF., Sci Adv. 9(): eade1463, 2023, PMID:36897941

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Multimerization of Zika Virus-NS5 Causes Ciliopathy and Forces Premature Neurogenesis.

Saade M, Ferrero DS, Blanco-Ameijeiras J, Gonzalez-Gobartt E, Flores-Mendez M, Ruiz-Arroyo VM, Martínez-Sáez E, Ramón Y Cajal S, Akizu N, Verdaguer N, Martí E., Cell Stem Cell. 27(): 920-936, 2020, PMID:33147489

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EZH2 regulates neuroepithelium structure and neuroblast proliferation by repressing p21.

Akizu N, García MA, Estarás C, Fueyo R, Badosa C, de la Cruz X, Martínez-Balbás MA., Open Biol. 6(4): 150227, 2016, PMID:27248655

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AMPD2 regulates GTP synthesis and is mutated in a potentially treatable neurodegenerative brainstem disorder.

Akizu N, Cantagrel V, Schroth J, Cai N, Vaux K, McCloskey D, Naviaux RK, Van Vleet J, Fenstermaker AG, Silhavy JL, Scheliga JS, Toyama K, Morisaki H, Sonmez FM, Celep F, Oraby A, Zaki MS, Al-Baradie R, Faqeih EA, Saleh MA, Spencer E, Rosti RO, Scott E, Nickerson E, Gabriel S, Morisaki T, Holmes EW, Gleeson JG., Cell. 154(3): 505-17, 2013, PMID:23911318

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Exome sequencing links corticospinal motor neuron disease to common neurodegenerative disorders.

Novarino G, Fenstermaker AG, Zaki MS, Hofree M, Silhavy JL, Heiberg AD, Abdellateef M, Rosti B, Scott E, Mansour L, Masri A, Kayserili H, Al-Aama JY, Abdel-Salam GMH, Karminejad A, Kara M, Kara B, Bozorgmehri B, Ben-Omran T, Mojahedi F, El Din Mahmoud IG, Bouslam N, Bouhouche A, Benomar A, Hanein S, Raymond L, Forlani S, Mascaro M, Selim L, Shehata N, Al-Allawi N, Bindu PS, Azam M, Gunel M, Caglayan A, Bilguvar K, Tolun A, Issa MY, Schroth J, Spencer EG, Rosti RO, Akizu N, Vaux KK, Johansen A, Koh AA, Megahed H, Durr A, Brice A, Stevanin G, Gabriel SB, Ideker T, Gleeson JG., Science. 343(6170): 506-11, 2014, PMID:24482476

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Biallelic mutations in SNX14 cause a syndromic form of cerebellar atrophy and lysosome-autophagosome dysfunction.

Akizu N, Cantagrel V, Zaki MS, Al-Gazali L, Wang X, Rosti RO, Dikoglu E, Gelot AB, Rosti B, Vaux KK, Scott EM, Silhavy JL, Schroth J, Copeland B, Schaffer AE, Gordts PL, Esko JD, Buschman MD, Field SJ, Napolitano G, Abdel-Salam GM, Ozgul RK, Sagıroglu MS, Azam M, Ismail S, Aglan M, Selim L, Mahmoud IG, Abdel-Hadi S, Badawy AE, Sadek AA, Mojahedi F, Kayserili H, Masri A, Bastaki L, Temtamy S, Müller U, Desguerre I, Casanova JL, Dursun A, Gunel M, Gabriel SB, de Lonlay P, Gleeson JG., Nat Genet. 47(5): 528-34, 2015, PMID:25848753

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