Abstract

Objectives: With an estimated seven to ten million sufferers worldwide, Parkinson’s disease (PD) is the second most common age-related neurodegenerative disorder. Progress in elucidating its causes has been slow, partly due to the lack of human-relevant models. Similarly, while the contribution of iron is increasingly advocated, identifying its role in disease progression remains challenging mainly due to the lack of valid model. In this study, we created Parkinson-like conditions in a human neuron model and conducted preliminary studies on iron-related parameters to assess whether these cells replicated iron accumulation observed in Parkinsonism. Methods: ReNcell VM (human neural progenitor) were differentiated into dopaminergic neurons (dDCNs) and treated with neurotoxin 6-hydroxy dopamine (100 μM) to mimic Parkinsonism. Total intracellular, mitochondrial and cytoplasmic iron was measured by ferrozine assay. Expression of iron-related genes TFRC, SLC40A1, HAMP and SLC25A37 were assessed through real-time PCR. Results: Data showed that the treated dDCNs accumulated iron over time and exceeded levels measured in untreated dDCNs by 2.5-fold at 48 h (p<0.02). Following the treatment, the treated cells showed lower expression of TFRC (p<0.05), but substantially higher mRNA expressions of SLC40A1 (9-fold; p<0.02) and HAMP (5.7-fold; p<0.05), along with higher intracellular iron (p<0.05). Higher iron accumulation in the mitochondria than cytosol (p<0.05), was also observed with increased expression of the mitochondrial iron-importer SLC25A37 (p=0.08). Conclusion: Our Parkinsonian model demonstrates iron accumulation and elevated HAMP expression as previously described in PD phenotype. The observed mitochondrial iron shuttling, which is proposed to be one of the primary contributors of oxidative stress in PD, calls for further investigation. The differences observed in distribution of iron in our human model and with the expression of major iron-related proteins, indicate that our model reproduces the disease state successfully, and suggests that further study could help in advancing our understanding of PD.

Highlights

  • With millions of sufferers world-wide, Parkinson’s disease (PD) is characterized by the gradual death of dopamine- producing neurons, which clinically manifests in impaired motor function and mobility

  • The differences observed in distribution of iron in our human model and with the expression of major iron-related proteins, indicate that our model reproduces the disease state successfully, and suggests that further study could help in advancing our understanding of PD

  • Whereas in the haemochromatotic patients, a 10-20-fold increase in iron stores seem to be necessary before clinical manifestations are observed, only a 2-fold increase in iron content in substantia nigra pars compacta (SNPC) of PD patients have been proposed to be sufficient for disease progression [5]

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Summary

Introduction

With millions of sufferers world-wide, Parkinson’s disease (PD) is characterized by the gradual death of dopamine- producing neurons, which clinically manifests in impaired motor function and mobility. Whereas in the haemochromatotic patients, a 10-20-fold increase in iron stores seem to be necessary before clinical manifestations are observed, only a 2-fold increase in iron content in SNPC of PD patients have been proposed to be sufficient for disease progression [5]. While this highlights the significance of iron content variation in the brain, the severity of its impact and the progression of PD in human are incompletely understood. This lack of understanding is partly due to the lack of human-relevant models, with the majority of studies being conducted on animal models that are unable to fully mimic the human PD pathophysiology

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