IPSC-based Modeling of THD Recapitulates Disease Phenotypes and Reveals Neuronal Malformation

Overview

Journal EMBO Mol Med

Specialty Molecular Biology

Date 2023 Feb 6

PMID 36740977

Authors

Alba Tristan-Noguero

Irene Fernandez-Carasa

Carles Calatayud

Cristina Bermejo-Casadesus

Meritxell Pons-Espinal

Arianna Colini Baldeschi

Leticia Campa

Francesc Artigas

Analia Bortolozzi

Rosario Domingo-Jimenez

Salvador Ibanez

Merce Pineda

Rafael Artuch

Angel Raya

Angels Garcia-Cazorla

Antonella Consiglio

Affiliations

Soon will be listed here.

Abstract

Tyrosine hydroxylase deficiency (THD) is a rare genetic disorder leading to dopaminergic depletion and early-onset Parkinsonism. Affected children present with either a severe form that does not respond to L-Dopa treatment (THD-B) or a milder L-Dopa responsive form (THD-A). We generated induced pluripotent stem cells (iPSCs) from THD patients that were differentiated into dopaminergic neurons (DAn) and compared with control-DAn from healthy individuals and gene-corrected isogenic controls. Consistent with patients, THD iPSC-DAn displayed lower levels of DA metabolites and reduced TH expression, when compared to controls. Moreover, THD iPSC-DAn showed abnormal morphology, including reduced total neurite length and neurite arborization defects, which were not evident in DAn differentiated from control-iPSC. Treatment of THD-iPSC-DAn with L-Dopa rescued the neuronal defects and disease phenotype only in THDA-DAn. Interestingly, L-Dopa treatment at the stage of neuronal precursors could prevent the alterations in THDB-iPSC-DAn, thus suggesting the existence of a critical developmental window in THD. Our iPSC-based model recapitulates THD disease phenotypes and response to treatment, representing a promising tool for investigating pathogenic mechanisms, drug screening, and personalized management.

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iPSC-based modeling of THD recapitulates disease phenotypes and reveals neuronal malformation.

Tristan-Noguero A, Fernandez-Carasa I, Calatayud C, Bermejo-Casadesus C, Pons-Espinal M, Colini Baldeschi A EMBO Mol Med. 2023; 15(3):e15847.

PMID: 36740977 PMC: 9994475. DOI: 10.15252/emmm.202215847.

References

Bruggemann N, Spiegler J, Hellenbroich Y, Opladen T, Schneider S, Stephani U . Beneficial prenatal levodopa therapy in autosomal recessive guanosine triphosphate cyclohydrolase 1 deficiency. Arch Neurol. 2012; 69(8):1071-5. DOI: 10.1001/archneurol.2012.104. View

Datla K, Blunt S, Dexter D . Chronic L-DOPA administration is not toxic to the remaining dopaminergic nigrostriatal neurons, but instead may promote their functional recovery, in rats with partial 6-OHDA or FeCl(3) nigrostriatal lesions. Mov Disord. 2001; 16(3):424-34. DOI: 10.1002/mds.1091. View

Ishikawa T, Imamura K, Kondo T, Koshiba Y, Hara S, Ichinose H . Genetic and pharmacological correction of aberrant dopamine synthesis using patient iPSCs with BH4 metabolism disorders. Hum Mol Genet. 2016; 25(23):5188-5197. PMC: 5886044. DOI: 10.1093/hmg/ddw339. View

Tokuoka H, Muramatsu S, Sumi-Ichinose C, Sakane H, Kojima M, Aso Y . Compensatory regulation of dopamine after ablation of the tyrosine hydroxylase gene in the nigrostriatal projection. J Biol Chem. 2011; 286(50):43549-58. PMC: 3234829. DOI: 10.1074/jbc.M111.284729. View

Althini S, Bengtsson H, Usoskin D, Soderstrom S, Kylberg A, Lindqvist E . Normal nigrostriatal innervation but dopamine dysfunction in mice carrying hypomorphic tyrosine hydroxylase alleles. J Neurosci Res. 2003; 72(4):444-53. DOI: 10.1002/jnr.10606. View

Money K, Stanwood G . Developmental origins of brain disorders: roles for dopamine. Front Cell Neurosci. 2014; 7:260. PMC: 3867667. DOI: 10.3389/fncel.2013.00260. View

Rossignoli G, Kramer K, Lugara E, Alrashidi H, Pope S, De La Fuente Barrigon C . Aromatic l-amino acid decarboxylase deficiency: a patient-derived neuronal model for precision therapies. Brain. 2021; 144(8):2443-2456. PMC: 8418346. DOI: 10.1093/brain/awab123. View

Chu C, Plowey E, Dagda R, Hickey R, Cherra 3rd S, Clark R . Autophagy in neurite injury and neurodegeneration: in vitro and in vivo models. Methods Enzymol. 2009; 453:217-49. PMC: 2669321. DOI: 10.1016/S0076-6879(08)04011-1. View

Iravani M, McCreary A, Jenner P . Striatal plasticity in Parkinson's disease and L-dopa induced dyskinesia. Parkinsonism Relat Disord. 2011; 18 Suppl 1:S123-5. DOI: 10.1016/S1353-8020(11)70038-4. View

10.

Ortez C, Duarte S, Ormazabal A, Serrano M, Perez A, Pons R . Cerebrospinal fluid synaptic proteins as useful biomarkers in tyrosine hydroxylase deficiency. Mol Genet Metab. 2014; 114(1):34-40. DOI: 10.1016/j.ymgme.2014.10.014. View

11.

Arikkath J . Molecular mechanisms of dendrite morphogenesis. Front Cell Neurosci. 2013; 6:61. PMC: 3531598. DOI: 10.3389/fncel.2012.00061. View

12.

Tristan-Noguero A, Fernandez-Carasa I, Calatayud C, Bermejo-Casadesus C, Pons-Espinal M, Colini Baldeschi A . iPSC-based modeling of THD recapitulates disease phenotypes and reveals neuronal malformation. EMBO Mol Med. 2023; 15(3):e15847. PMC: 9994475. DOI: 10.15252/emmm.202215847. View

13.

Prots I, Grosch J, Brazdis R, Simmnacher K, Veber V, Havlicek S . α-Synuclein oligomers induce early axonal dysfunction in human iPSC-based models of synucleinopathies. Proc Natl Acad Sci U S A. 2018; 115(30):7813-7818. PMC: 6065020. DOI: 10.1073/pnas.1713129115. View

14.

Darmopil S, Muneton-Gomez V, de Ceballos M, Bernson M, Moratalla R . Tyrosine hydroxylase cells appearing in the mouse striatum after dopamine denervation are likely to be projection neurones regulated by L-DOPA. Eur J Neurosci. 2008; 27(3):580-92. DOI: 10.1111/j.1460-9568.2008.06040.x. View

15.

Escriba R, Ferrer-Lorente R, Raya A . Inborn errors of metabolism: Lessons from iPSC models. Rev Endocr Metab Disord. 2021; 22(4):1189-1200. PMC: 8724155. DOI: 10.1007/s11154-021-09671-z. View

16.

Chambers S, Fasano C, Papapetrou E, Tomishima M, Sadelain M, Studer L . Highly efficient neural conversion of human ES and iPS cells by dual inhibition of SMAD signaling. Nat Biotechnol. 2009; 27(3):275-80. PMC: 2756723. DOI: 10.1038/nbt.1529. View

17.

Moller L, Romstad A, Paulsen M, Hougaard P, Ormazabal A, Pineda M . Pre- and postnatal diagnosis of tyrosine hydroxylase deficiency. Prenat Diagn. 2005; 25(8):671-5. DOI: 10.1002/pd.1193. View

18.

Korner G, Noain D, Ying M, Hole M, Flydal M, Scherer T . Brain catecholamine depletion and motor impairment in a Th knock-in mouse with type B tyrosine hydroxylase deficiency. Brain. 2015; 138(Pt 10):2948-63. DOI: 10.1093/brain/awv224. View

19.

Zhou Q, Quaife C, Palmiter R . Targeted disruption of the tyrosine hydroxylase gene reveals that catecholamines are required for mouse fetal development. Nature. 1995; 374(6523):640-3. DOI: 10.1038/374640a0. View

20.

Willemsen M, Verbeek M, Kamsteeg E, de Rijk-van Andel J, Aeby A, Blau N . Tyrosine hydroxylase deficiency: a treatable disorder of brain catecholamine biosynthesis. Brain. 2010; 133(Pt 6):1810-22. DOI: 10.1093/brain/awq087. View