Iron Deposition Leads to Neuronal α-Synuclein Pathology by Inducing Autophagy Dysfunction

Abstract

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.

Macular Ganglion Cell Complex and Peripapillary Retinal Nerve Fiber Layer Thinning in Patients with Type-1 Gaucher Disease

“…Retinal ganglion cells—whose axons form the ON—are metabolically active and sensitive to neurodegenerative damage due to ischemia, mitochondrial dysfunction, oxidative stress and abnormal axonal transport [ 11 , 16 , 17 ]. Mechanisms of RGC death include apoptosis and necrosis [ 18 ].…”

“…The RGC somas reside in the ganglion cell layer (GCL) in the inner retina and it is their axons that form the retinal nerve fiber layer (RNFL) which comprise the optic nerve (ON). From the ON the visual information is transmitted via axons leading to the lateral geniculate body [ 11 ]. Damage to RGC along their course can be expressed as cell body or axon injury.…”

Effects of Transcranial Direct Current Stimulation on GABA and Glx in Children: A pilot study

“…They propose MRS measures of Glx lack sensitivity to consistently detect Glx changes following tDCS [4,28]. Several other studies report an absence of significant changes in Glx in response to a-tDCS at the site of stimulation with little speculation as to why [4,29,66,67,69]. It may be that tDCS influences Glx in a complex way that is network dependent.…”

Intrinsic network reactivity differentiates levels of consciousness in comatose patients

“…The inter-pretability of ERP studies involving a single sensory modality may be compromised due to etiological heterogeneity (Kotchoubey, 2017), and their robustness in differentiating various degrees of consciousness is subject to debate (Kotchoubey et al, 2005; Höller et al, 2011; Real et al, 2016). Alternatively, approaches involving direct (e.g., electromagnetic) stimulation of the cortex (Bagnato et al, 2012; Rosanova et al, 2012; Casali et al, 2013; Zhang et al, 2017), while conceptually more favorable, raise the instrumentation burden substantially and are thus not ideal for routine clinical assessment. More comprehensive reviews of the previous findings in detecting signs of consciousness using electrophysiological methods can be found in (Sitt et al, 2014; Rapp et al, 2015; Sebastiano et al, 2015; Cruse et al, 2016; Estraneo et al, 2016; Ragazzoni et al, 2017).…”

“…Our goal is to devise a strategy that can offer an EEG-based assessment of brain responsiveness in resting state, without the need for extrinsic stimulation. Although there have been previous attempts to reach this goal (Bai et al, 2017), these attempts have been mostly based on information-theoretic (Pollonini et al, 2010; Sarà & Pistoia, 2010; Gosseries et al, 2011; King et al, 2013; Marinazzo et al, 2014; Thul et al, 2016) or graph-theoretic (Lehembre et al, 2012; Leon-Carrion et al, 2012; Chennu et al, 2014; Höller et al, 2014; Varotto et al, 2014; Chennu et al, 2017; Numan et al, 2017) metrics, which do not provide direct information about the underlying neuronal dynamics. Furthermore, the majority of these studies focus on distinguishing minimally conscious patients from patients in vegetative state.…”