HGprt deficiency disrupts dopaminergic circuit development in a genetic mouse model of Lesch–Nyhan disease

Abstract

In Lesch–Nyhan disease (LND), deficiency of the purine salvage enzyme hypoxanthine guanine phosphoribosyl transferase (HGprt) leads to a characteristic neurobehavioral phenotype dominated by dystonia, cognitive deficits and incapacitating self-injurious behavior. It has been known for decades that LND is associated with dysfunction of midbrain dopamine neurons, without overt structural brain abnormalities. Emerging post mortem and in vitro evidence supports the hypothesis that the dopaminergic dysfunction in LND is of developmental origin, but specific pathogenic mechanisms have not been revealed. In the current study, HGprt deficiency causes specific neurodevelopmental abnormalities in mice during embryogenesis, particularly affecting proliferation and migration of developing midbrain dopamine (mDA) neurons. In mutant embryos at E14.5, proliferation was increased, accompanied by a decrease in cell cycle exit and the distribution and orientation of dividing cells suggested a premature deviation from their migratory route. An abnormally structured radial glia-like scaffold supporting this mDA neuronal migration might lie at the basis of these abnormalities. Consequently, these abnormalities were associated with an increase in area occupied by TH+ cells and an abnormal mDA subpopulation organization at E18.5. Finally, dopaminergic innervation was disorganized in prefrontal and decreased in HGprt deficient primary motor and somatosensory cortices. These data provide direct in vivo evidence for a neurodevelopmental nature of the brain disorder in LND. Future studies should not only focus the specific molecular mechanisms underlying the reported neurodevelopmental abnormalities, but also on optimal timing of therapeutic interventions to rescue the DA neuron defects, which may also be relevant for other neurodevelopmental disorders.

A new physiological medium uncovers biochemical and cellular alterations in Lesch-Nyhan disease fibroblasts

“…This could be relevant to understand LND physiopathology, since recently it has been reported that HPRT1 knock out mice present neurodevelopmental alterations during embryogenesis, affecting proliferation and migration of cells. Specifically, proliferation of developing midbrain dopamine (mDA neurons) was increased in the mutant embryo, accompanied with a deviation from their migratory route (Witteveen et al 2022 ).…”

Metabolic and neurobehavioral disturbances induced by purine recycling deficiency inDrosophila

“…However, none of these models recapitulated the full LND syndrome and, particularly, motor or neurobehavioral symptoms as a consequence of HGPRT deficiency. To date, the causes of the neurobehavioral impairments in LND are not yet clearly elucidated and the disease is still incurable (Fu et al 2014; Bell et al 2016; López et al 2020; Bell et al 2021; Witteveen et al 2022). Here we used two different strategies to develop new models of this disease in Drosophila , a useful organism to conduct genetic and pharmacological studies.. First, we show that Aprt deficiency induces both metabolic and neurobehavioral disturbances in Drosophila , similar to the loss of HGPRT, but not APRT, activity in humans.…”

“…How HGPRT deficiency can cause such dramatic neurobehavioral troubles in LND patients still remains a crucial question. To date, cellular (Smith & Friedman 2000; Torres et al 2004; Ceballos-Picot et al 2009; Cristini et al 2010; Guibinga et al 2012; Sutcliffe et al 2021) and rodent (Finger et al 1988; Dunnett et al 1989; Jinnah et al 1993; Meek et al 2016; Witteveen et al 2022) models only focused on the consequences of HGPRT deficiency to phenocopy the disease. Such an approach was justified by the fact that the lower the residual activity of mutant HGPRT, the more severe the symptoms are in patients (Fu and Jinnah 2012.…”

Metabolic patterns in brain 18F-fluorodeoxyglucose PET relate to aetiology in paediatric dystonia

“…In murine models FDG-PET brain imaging has been shown to be a valuable tool in deciphering disease mechanisms and potential for assessing the in vivo efficacy of novel therapeutics. 63 , 64 Using such imaging techniques in already established models of paediatric dystonias 65 , 66 would be an obvious research avenue to pursue in future studies. Follow-up pre- and post-DBS insertion FDG-PET imaging studies in childhood dystonia cohorts might also offer insights of regional brain metabolism alterations in responder and non-responder subgroups.…”