Deferiprone Rescues Behavioral Deficits Induced by Mild Iron Exposure in a Mouse Model of Alpha-Synuclein Aggregation

Eleonora Carboni,Mathias Bähr,Vivian Dambeck,Lars Tönges,Paul Lingor,Lars Tatenhorst,Elisabeth Barski

doi:10.1007/s12017-017-8447-9

Abstract

Parkinson’s disease (PD) is the most common neurodegenerative movement disorder, and its causes remain unknown. A major hallmark of the disease is the increasing presence of aggregated alpha-synuclein (aSyn). Furthermore, there is a solid consensus on iron (Fe) accumulation in several regions of PD brains during disease progression. In our study, we focused on the interaction of Fe and aggregating aSyn in vivo in a transgenic mouse model overexpressing human aSyn bearing the A53T mutation (prnp.aSyn.A53T). We utilized a neonatal iron-feeding model to exacerbate the motor phenotype of the transgenic mouse model. Beginning from day 100, mice were treated with deferiprone (DFP), a ferric chelator that is able to cross the blood–brain barrier and is currently used in clinics as treatment for hemosiderosis. Our paradigm resulted in an impairment of the learning abilities in the rotarod task and the novel object recognition test. DFP treatment significantly improved the performance in both tasks. Although this was not accompanied by alterations in aSyn aggregation, our results support DFP as possible therapeutic option in PD.

Highlights

Parkinson’s disease (PD) is the most common neurodegenerative movement disorder (Pringsheim et al 2014)
We focused on the interaction of Fe and aggregating aSyn in vivo in a transgenic mouse model overexpressing human aSyn bearing the A53T mutation
In order to assess the effects of Fe in the A53T mouse model on the behavioral level, animals were tested on the rotarod as well as on the CatwalkTM gait analysis system

Summary

Introduction

Parkinson’s disease (PD) is the most common neurodegenerative movement disorder (Pringsheim et al 2014). Aging is regarded as a major risk factor and, in a society with increasing life expectancy, PD represents a massive socioeconomic burden, where new treatment approaches are urgently needed. Rare hereditary forms of PD exist (Singleton et al 2013). Duplications, triplications as well as single point mutations in the genetic sequence of alpha-synuclein (aSyn) have been found in families with inherited forms of PD (Kasten and Klein 2013; Polymeropoulos et al 1997). Lewy bodies (LB) represent a hallmark of the disease in both idiopathic and some hereditary forms, and they consist mainly of aSyn aggregates (Spillantini et al 1997), which underlines a prominent role of this protein in PD etiology

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