Growing evidence has indicated that iron deposition in the substantia nigra plays an important role in Parkinson’s disease (PD). However, the underlying mechanism is still elusive. Using primary dopaminergic neurons and SH-SY5Y cells cultured in vitro, we observed that iron loading increased α-synuclein and reactive oxygen species (ROS) levels in these cells but did not affect the intracellular α-synuclein mRNA levels. Furthermore, iron loading significantly downregulated Beclin-1 levels and decreased the ratio of microtubule-associated protein 1 light chain 3 isoforms (LC3 II/LC3 I). However, a significant change in the levels of autophagy-related gene 5 (Atg5) was not observed in either neurons or SH-SY5Y cells after iron treatment. After treatment with rapamycin, the iron loading-induced increase in the α-synuclein level was significantly reversed and ROS generation was alleviated in both cultured neurons and SH-SY5Y cells. These results indicate that the inhibition of autophagy is critical for the pathological alterations in α-synuclein induced by iron loading. Moreover, treatment with vitamin E did not affect the increase in the α-synuclein levels but significantly eliminated the iron-induced ROS production. Together, our study shows that autophagy dysfunction contributes to iron-induced α-synuclein pathology.

Background We aimed to investigate neuromelanin‐sensitive magnetic resonance imaging (NM‐MRI) features in the locus coeruleus of de novo Parkinson's disease patients with different cognitive states and to determine whether these features are associated with cognitive impairment. Methods Three groups of subjects were recruited in this study, including patients with de novo PD with mild cognitive impairment (n = 23), patients with de novo PD without cognitive impairment (n = 48), and control subjects (n = 32). All subjects underwent clinical evaluations, as well as MRI scanning. The contrast‐to‐noise ratio of the locus coeruleus in the neuromelanin‐sensitive MRI images and cortical thickness were measured. Results The contrast‐to‐noise ratio of the locus coeruleus in PD patients with mild cognitive impairment was significantly lower than that of controls (P = 0.016). The contrast‐to‐noise ratio of the locus coeruleus for PD patients without cognitive impairment was intermediate between that of controls and PD patients with mild cognitive impairment. Furthermore, multiple linear regression analysis showed that the contrast‐to‐noise ratio of the locus coeruleus was negatively associated with performance on the Trail Making Test B in all PD patients, controlling for age, sex, years of education, the Unified Parkinson's Disease Rating Scale motor scores from right upper limb, Geriatric Depression Rating Scales scores, Rapid Eye Movement Sleep Behavior Disorder Screening Questionnaire scores, and cortical thickness. Conclusions Dysfunction of the locus coeruleus neurons may partly contribute to the decline in executive function in early de novo PD. In the future, the locus coeruleus‐norepinephrine system might be targeted for early‐intervention strategies in PD patients. © 2019 International Parkinson and Movement Disorder Society