Altered heparan sulfate metabolism during development triggers dopamine-dependent autistic-behaviours in models of lysosomal storage disorders

Maria Risi, Michele Tufano, Filomena Grazia Alvino, Maria Grazia Ferraro, Giulia Torromino, Ylenia Gigante, Jlenia Monfregola, Elena Marrocco, Salvatore Pulcrano, Lea Tunisi, Claudia Lubrano, Dulce Papy-Garcia, Yaakov Tuchman, Alberto Salleo, Francesca Santoro, Gian Carlo Bellenchi, Luigia Cristino, Andrea Ballabio, Alessandro Fraldi and Elvira Leonibus ()
Additional contact information
Maria Risi: Telethon Institute of Genetics and Medicine
Michele Tufano: Telethon Institute of Genetics and Medicine
Filomena Grazia Alvino: Telethon Institute of Genetics and Medicine
Maria Grazia Ferraro: Telethon Institute of Genetics and Medicine
Giulia Torromino: Telethon Institute of Genetics and Medicine
Ylenia Gigante: Telethon Institute of Genetics and Medicine
Jlenia Monfregola: Telethon Institute of Genetics and Medicine
Elena Marrocco: Telethon Institute of Genetics and Medicine
Salvatore Pulcrano: Institute of Genetics and Biophysics, CNR
Lea Tunisi: Institute of Biomolecular Chemistry, CNR
Claudia Lubrano: Center for Advanced Biomaterials for Healthcare, Istituto Italiano di Tecnologia
Dulce Papy-Garcia: Université Paris-Est Créteil Val de Marne (UPEC)
Yaakov Tuchman: Stanford University
Alberto Salleo: Stanford University
Francesca Santoro: Center for Advanced Biomaterials for Healthcare, Istituto Italiano di Tecnologia
Gian Carlo Bellenchi: Institute of Genetics and Biophysics, CNR
Luigia Cristino: Institute of Biomolecular Chemistry, CNR
Andrea Ballabio: Telethon Institute of Genetics and Medicine
Alessandro Fraldi: Telethon Institute of Genetics and Medicine
Elvira Leonibus: Telethon Institute of Genetics and Medicine

Nature Communications, 2021, vol. 12, issue 1, 1-17

Abstract: Abstract Lysosomal storage disorders characterized by altered metabolism of heparan sulfate, including Mucopolysaccharidosis (MPS) III and MPS-II, exhibit lysosomal dysfunctions leading to neurodegeneration and dementia in children. In lysosomal storage disorders, dementia is preceded by severe and therapy-resistant autistic-like symptoms of unknown cause. Using mouse and cellular models of MPS-IIIA, we discovered that autistic-like behaviours are due to increased proliferation of mesencephalic dopamine neurons originating during embryogenesis, which is not due to lysosomal dysfunction, but to altered HS function. Hyperdopaminergia and autistic-like behaviours are corrected by the dopamine D1-like receptor antagonist SCH-23390, providing a potential alternative strategy to the D2-like antagonist haloperidol that has only minimal therapeutic effects in MPS-IIIA. These findings identify embryonic dopaminergic neurodevelopmental defects due to altered function of HS leading to autistic-like behaviours in MPS-II and MPS-IIIA and support evidence showing that altered HS-related gene function is causative of autism.

Date: 2021
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DOI: 10.1038/s41467-021-23903-5

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