Progressive dopaminergic cell loss with unilateral-to-bilateral progression in a genetic model of Parkinson disease

Abstract

DJ-1 mutations cause autosomal recessive early-onset Parkinson disease (PD). We report a model of PD pathology: the DJ1-C57 mouse. A subset of DJ-1–nullizygous mice, when fully backcrossed to a C57BL/6J background, display dramatic early-onset unilateral loss of dopaminergic (DA) neurons in their substantia nigra pars compacta , progressing to bilateral degeneration of the nigrostriatal axis with aging. In addition, these mice exhibit age-dependent bilateral degeneration at the locus ceruleus nucleus and display mild motor behavior deficits at aged time points. These findings effectively recapitulate the early stages of PD. Therefore, the DJ1-C57 mouse provides a tool to study the preclinical aspects of neurodegeneration. Importantly, by exome sequencing, we identify candidate modifying genes that segregate with the phenotype, providing potentially critical clues into how certain genes may influence the penetrance of DJ-1–related degeneration in mice.

Regulation of dopamine presynaptic markers and receptors in the striatum of DJ-1 and Pink1 knockout rats

“…In DJ-1 –nullizygous mice recently created by Rousseaux et al [13], an increase in murine osteosarcoma viral oncogene homolog B (ΔFosB), a striatal postsynaptic marker was observed; this has also been reported in PD patients and neurotoxin-induced animal models of PD, indicating that there is a similar compensatory response in DJ-1 knockout mice. Our data suggests that the upregulation of striatal D 2 receptors possibly be one of the postsynaptic compensatory responses upon neuronal loss in SNpc in DJ-1 and Pink1 knockout rats.…”

“…Previously, DAT density in synaptosomes of DJ-1 knockout mice, which lack dopaminergic neuronal loss, has been reported to be either unchanged [5, 6] or increased [8]. A new DJ-1 –nullizygous mouse model was recently created which shows significant dopaminergic cell loss as early as 2 months of age but without clear loss of striatal dopamine termini by TH staining; this has been attributed to sprouting of neurites within the nigrostriatal pathway [13]. This report is in line with our findings showing no significant reduction of dopamine pre-synaptic markers although there was a significant neuronal loss in SNpc in DJ-1 knockout rats.…”

“…A DJ-1 –nullizygous mouse was recently created which demonstrated progressive dopaminergic cell loss [13]. However, neither loss of striatal dopamine termini nor increase of striatal postsynaptic marker ΔFBJ was observed in this new model, indicating that both pre- and postsynaptic dopamine components are involved in compensatory regulation [13]. Unfortunately, the density of dopamine presynaptic markers and receptors was not determined in this study.…”

“…One postmortem neuropathological study showed neuronal loss in the SNpc in familial PD patients with Pink1 mutations [11]. A DJ-1 –nullizygous mouse was recently created which demonstrated progressive dopaminergic cell loss [13]. However, neither loss of striatal dopamine termini nor increase of striatal postsynaptic marker ΔFBJ was observed in this new model, indicating that both pre- and postsynaptic dopamine components are involved in compensatory regulation [13].…”

Overexpression of DJ-1 protects against C2-ceramide-induced neuronal death through activation of the PI3K/AKT pathway and inhibition of autophagy

“…Thus, dysfunction of DJ-1 protein could lead to dopaminergic neurons loss [6], whereas overexpression of DJ-1 acts as a neuroprotective mechanism [7]. However, the function of DJ-1 within mitochondria, its relationship to the neuronal survival pathway mediated by PI3K/AKT is still unclear.…”