Iron dyshomeostasis and enhanced myelination in the prefrontal cortex and ventral basal ganglia of a DJ-1 knockout model of early-onset Parkinson's disease.
Iron dyshomeostasis and enhanced myelination in the prefrontal cortex and ventral basal ganglia of a DJ-1 knockout model of early-onset Parkinson's disease.
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Original abstract
BACKGROUND: Early-onset Parkinson's disease (EOPD) differs from late-onset PD in clinical progression and neurodegenerative patterns. DJ-1 mutations are a known genetic cause of EOPD. Despite the recognized role of iron dyshomeostasis in PD pathogenesis, its spatial distribution and associated tissue alterations in EOPD remain unclear. This study investigated whole-brain iron distribution and related pathological changes in 9-month-old DJ-1-/- mice. METHODS: In vivo quantitative susceptibility mapping (QSM) was performed to characterize whole-brain iron distribution, complemented by ex vivo laser ablation inductively coupled plasma mass spectrometry imaging (LA-ICP-MSI) to validate abnormal iron deposition in secondary motor cortex (M2) and ventral orbital cortex (VO). Anatomical magnetic resonance imaging (MRI), diffusion tensor imaging (DTI), Western blotting, and immunohistochemistry were used to assess brain morphology, microstructural alterations, iron-related proteins, myelination, oxidative stress, and dopaminergic integrity. RESULTS: DJ-1-/- mice exhibited motor deficits without significant nigrostriatal dopaminergic degeneration. QSM revealed significantly increased magnetic susceptibility in the M2, VO, the core of nucleus accumbens (NAc), and ventral pallidum (VP). Elevated iron content in M2 and VO was further verified by LA-ICP-MSI. Regions with increased iron deposition were also shown to exhibit altered ferritin composition, increased fractional anisotropy and myelin basic protein expression, and elevated oxidative stress. CONCLUSION: 9-month-old DJ-1-/- mice show region-specific iron dyshomeostasis in parts of the prefrontal cortex and ventral basal ganglia, which precedes overt nigrostriatal dopaminergic degeneration. Iron accumulation, myelin remodeling, and oxidative stress occur in parallel in the affected brain regions, and may increase metabolic and redox demands, thereby contributing to early functional impairment independent of dopaminergic neurodegeneration.