Modeling Parkinson's Disease Through Combined DJ-1 Deficiency and Noradrenergic Degeneration

Parkinson's disease (PD) is characterized by progressive degeneration of the nigrostriatal dopaminergic system while increasing evidence indicates that early pathology also involves the locus coeruleus (LC) and the noradrenergic system. However, whether LC degeneration increases dopaminergic vulnerability in genetically susceptible background remains poorly understood. Here, we investigated the impact of selective noradrenergic depletion on behavioral and neuropathological phenotypes in DJ-1 knockout (KO) mice, a model of familial PD. DJ-1 KO and wild-type (WT) mice received the selective LC neurotoxin DSP-4 (50 mg/kg) to induce noradrenergic degeneration, followed by a battery of motor and non-motor behavioral assessments and histological analysis of the LC and nigrostriatal system. DSP-4 induced approximately 80-85% LC neuronal loss, confirming effective noradrenergic lesioning. While DSP-4-treated WT mice displayed relatively mild behavioral alterations, its combination with DJ-1 deficiency produced marked impairments, including increased anxious- and depressive-like behaviors, enhanced contextual fear responses, and deficits in motor coordination and balance. At the nigrostriatal level, DJ-1 KO mice already exhibited reduced TH-positive neurons in the substantia nigra pars compacta (SNc), whereas combined DJ-1 deficiency and DSP-4 treatment produced a further significant reduction in striatal TH density, without significant additional loss of SNc TH-positive neurons. These findings indicate that LC noradrenergic degeneration selectively exacerbates dopaminergic terminal pathology in the DJ-1-deficient background, suggesting increased vulnerability of the nigrostriatal system to noradrenergic loss. Overall, our data identify LC degeneration as a modifier of both motor and non-motor phenotypes associated with DJ-1 deficiency and provide experimental support for a functional interaction between the noradrenergic and nigrostriatal systems in PD.