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

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-r...

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Detalles Bibliográficos
Autores principales: De Risi, Maria, Tufano, Michele, Alvino, Filomena Grazia, Ferraro, Maria Grazia, Torromino, Giulia, Gigante, Ylenia, Monfregola, Jlenia, Marrocco, Elena, Pulcrano, Salvatore, Tunisi, Lea, Lubrano, Claudia, Papy-Garcia, Dulce, Tuchman, Yaakov, Salleo, Alberto, Santoro, Francesca, Bellenchi, Gian Carlo, Cristino, Luigia, Ballabio, Andrea, Fraldi, Alessandro, De Leonibus, Elvira
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8190083/
https://www.ncbi.nlm.nih.gov/pubmed/34108486
http://dx.doi.org/10.1038/s41467-021-23903-5
Descripción
Sumario: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.