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

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.

Impaired neural differentiation of MPS IIIA patient induced pluripotent stem cell-derived neural progenitor cells

“…As MPS IIIA HS GAG is freely diffusible the FGF2 bound to it may no longer be localized where it can bind to the FGFR. This finding is also supported by de Risi (2021) who showed using the same MTS assay in Baf32 cells that MPS IIIA HS extracts failed to induce proliferation mediated by FGF2 in comparison to wildtype HS [66] . Thus the abnormal turnover of HS in MPS IIIA and the accumulation of high levels of abnormally structured HS in the CNS clearly interrupts the delicate balance between FGF2 growth factor/growth factor receptor/growth factor co-receptor in NPC proliferation.…”

“…A very recent study generated a SH-SY5Y neuroblastoma cell line based MPS IIIA model using CRISPR-Cas9 disruption of SGSH. These neural progenitor-like cells displayed increased proliferation which was reduced when wildtype heparan sulphate was introduced into the cell media [66] , suggesting a role for HS in proliferative ability and neurodifferention of SH-SY5Y cells. Further evidence from de Pasquale et al (2021) using a NAGLU silenced neuroblastoma model of MPS IIIB highlights a key role for HSPGs in neurite outgrowth using the specific growth factor NK1 which is proposed to bind with high affinity the extracellular accumulated HS [68] .…”

The Development of the Mesoprefrontal Dopaminergic System in Health and Disease

“…This hyperdopaminergic state in MPS IIIa mice appears to be caused by developmental changes in the DA system: increased proliferation of mDA progenitors results in an increased number of mDA neurons in the SNpc and the VTA in the adult brain. Moreover, the same study shows that autisticlike behaviors and increased DA cell number are also present in a mouse model for a different type of MPS (MPS-II) (Risi et al, 2021). While this study suggests that altered development of the mDA system may be one of the causes of autism-like behaviors, it has not been investigated whether the increase in VTA neurons in these animal models leads also to alterations in the mesoprefrontal DA system.…”

Lmx1a-Dependent Activation of miR-204/211 Controls the Timing of Nurr1-Mediated Dopaminergic Differentiation

“…Fresh single-cell suspensions obtained by the Trypsin-based enzymatic solution as described above were centrifuged 5 × 100× g and plated as in De Risi et al, 2021 [78] in a Neurobasal medium (NBM, Gibco, Milan, Italy), supplemented with B27 (Invitrogen, Milan, Italy), 2 mM L-glutamine (Gibco), penicillin, and streptomycin 10U + 10µg/mL (Pen/Strep, Sigma) with the addition of bFGF (20 ng/mL, Sigma), FGF8 (10 ng/mL, Sigma), and SHH (50 ng/mL; R&D systems, Abingdon-on-Thames, UK) at a density of 4 × 10 4 cells/cm 2 on poly-D-lysine (PDL) coated multiwells (15 µg/mL PDL for 1 h at 37 • C; Sigma).…”

“…iDA neurons were generated from Mouse embryonic fibroblasts (MEFs) as previously described [36,78,80]. In brief, MEFs isolated from E14.5 mice embryos were infected with lentiviral particles coding for the TFs Ascl1, Nurr1, and Lmx1a in DMEM (Gibco) supplemented with 10% FBS, Pen/Strep, and doxycycline (4 µg/mL).…”