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.
Currently, the etiology of Alzheimer’s disease (AD) is still elusive. Central insulin resistance has been determined to play an important role in the progress of AD. However, the mechanism underlying the development of disrupted insulin signaling pathways in AD is unclear. Suppressor of cytokine signaling 3 (SOCS3) is a member of the SOCS protein family that acts as a negative modulator of insulin signaling in sensitive tissues, such as hepatocytes and adipocytes. However, little is known about its role in neurological diseases. Recent evidence indicates that the level of SOCS3 is increased in the brains of individuals with AD, especially in areas with amyloid beta deposition, suggesting that SOCS3 may regulate the central insulin signaling pathways in AD. Here, we discuss the potential role of SOCS3 in AD and speculate that SOCS3 may be a promising therapeutic target for the treatment of AD.
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