Altered heparan sulfate metabolism during development triggers dopamine-dependent autistic-behaviours in models of lysosomal storage disorders
Authors: M. De Risi, M. Tufano, F.G. Alvino, M. G. Ferraro, G.Torromino, Y. Gigante, J. Monfregola, E. Marrocco, S. Pulcrano, L. Tunisi, C. Lubrano, D. Papy-Garcia, Y. Tuchman, A. Salleo, F. Santoro, G. C. Bellenchi, L. Cristino, A. Ballabio, A. Fraldi, E. De Leonibus.
Year: 2021
Sources: Nature Communications
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.
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