Abstract
Iron deposition is present in main lesion areas in the brains of patients with Parkinson’s disease (PD) and an abnormal iron content may be associated with dopaminergic neuronal cytotoxicity and degeneration in the substantia nigra of the midbrain. However, the cause of iron deposition and its role in the pathological process of PD are unclear. In the present study, we investigated the effects of the nasal mucosal delivery of synthetic human α-synuclein (α-syn) preformed fibrils (PFFs) on the pathogenesis of PD in Macaca fascicularis. We detected that iron deposition was clearly increased in a time-dependent manner from 1 to 17 months in the substantia nigra and globus pallidus, highly contrasting to other brain regions after treatments with α-syn PFFs. At the cellular level, the iron deposits were specifically localized in microglia but not in dopaminergic neurons, nor in other types of glial cells in the substantia nigra, whereas the expression of transferrin (TF), TF receptor 1 (TFR1), TF receptor 2 (TFR2), and ferroportin (FPn) was increased in dopaminergic neurons. Furthermore, no clear dopaminergic neuron loss was observed in the substantia nigra, but with decreased immunoreactivity of tyrosine hydroxylase (TH) and appearance of axonal swelling in the putamen. The brain region-enriched and cell-type-dependent iron localizations indicate that the intranasal α-syn PFFs treatment-induced iron depositions in microglia in the substantia nigra may appear as an early cellular response that may initiate neuroinflammation in the dopaminergic system before cell death occurs. Our data suggest that the inhibition of iron deposition may be a potential approach for the early prevention and treatment of PD.
Highlights
Parkinson’s disease (PD) is a common neurodegenerative disease
As iron deposition increased in the substantia nigra but the deposits were mostly localized in microglia rather than dopaminergic neurons, we examined how microglia with a high iron content might affect dopaminergic neurons
Iron plays a key role in this process; the excessive deposition of iron may be involved in the degenerative death process of dopaminergic neurons in PD32,41,42
Summary
The motor symptoms of PD include resting tremor, bradykinesia, rigidity, and postural abnormalities[1]. PD patients can exhibit different nonmotor symptoms, such as constipation[2], depression[3], and cognitive decline[4], which usually precede the motor. The main pathological features of PD include the degeneration of dopaminergic neurons in the substantia nigra and the appearance of Lewy bodies, Luria-Bertani medium (LBs) in surviving neurons[6]. The protein αsynuclein (α-syn) is a constitutive component of LBs that is normally a monomeric protein under physiological conditions but forms amyloid fibrils under pathological conditions. The aggregation of α-syn is closely associated with PD progression. Emerging evidence has shown that the pathological propagation of α-syn in the brain may contribute to PD progression[7].
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