The novel compound PBT434 prevents iron mediated neurodegeneration and alpha-synuclein toxicity in multiple models of Parkinson\u2019s disease

David I Finkelstein,Jack Parsons,E C L Gautier ,Philip Doble ,Sherie Ma ,Izabela A Zawisza ,Jessica L Billings,Ewa Kurowska,Scott Ayton,Simon Wilkins,Simon Crawford,Ashley I Bush,David M Shackleford,Kevin J Barnham,Paul A Adlard,Susan A Charman,Andrew L Gundlach,Penny Huggins,Wojciech Bal,Colin L Masters,Amelia Sedjahtera,Dominic J Hare,Robert A Cherny

doi:10.1186/s40478-017-0456-2

Abstract

Elevated iron in the SNpc may play a key role in Parkinson’s disease (PD) neurodegeneration since drug candidates with high iron affinity rescue PD animal models, and one candidate, deferirpone, has shown efficacy recently in a phase two clinical trial. However, strong iron chelators may perturb essential iron metabolism, and it is not yet known whether the damage associated with iron is mediated by a tightly bound (eg ferritin) or lower-affinity, labile, iron pool. Here we report the preclinical characterization of PBT434, a novel quinazolinone compound bearing a moderate affinity metal-binding motif, which is in development for Parkinsonian conditions. In vitro, PBT434 was far less potent than deferiprone or deferoxamine at lowering cellular iron levels, yet was found to inhibit iron-mediated redox activity and iron-mediated aggregation of α-synuclein, a protein that aggregates in the neuropathology. In vivo, PBT434 did not deplete tissue iron stores in normal rodents, yet prevented loss of substantia nigra pars compacta neurons (SNpc), lowered nigral α-synuclein accumulation, and rescued motor performance in mice exposed to the Parkinsonian toxins 6-OHDA and MPTP, and in a transgenic animal model (hA53T α-synuclein) of PD. These improvements were associated with reduced markers of oxidative damage, and increased levels of ferroportin (an iron exporter) and DJ-1. We conclude that compounds designed to target a pool of pathological iron that is not held in high-affinity complexes in the tissue can maintain the survival of SNpc neurons and could be disease-modifying in PD.

Highlights

Idiopathic Parkinson’s disease (PD) is characterized by loss of the neurons of the substantia nigra pars compacta (SNpc) and the presence of intracellular Lewy bodies composed primarily of fibrillar deposits of the synaptic protein α-synuclein
As PBT434 has greater than 20 orders of magnitude less affinity for iron than these classical chelators, it was thought valuable to evaluate whether the large difference in affinities might be reflected in the ability of the respective compounds to promote the efflux of Fe from biological tissues
We found that MPTP treatment significantly reduced levels of the presynaptic protein synaptophysin, and this lesion was abolished by treatment with PBT434 (30 mg/kg/day) (Fig. 4e)

Summary

Introduction

Idiopathic Parkinson’s disease (PD) is characterized by loss of the neurons of the substantia nigra pars compacta (SNpc) and the presence of intracellular Lewy bodies composed primarily of fibrillar deposits of the synaptic protein α-synuclein. The physiological function of α-synuclein is poorly understood, but genetic evidence strongly implicates this highly-expressed protein in the pathological α-synuclein may be neurotoxic in the fibrillar state or soluble oligomeric species [20, 42]. It is expressed throughout the brain, so the selective vulnerability of the SNpc in PD indicates other local factors may be involved in toxicity. Dysregulation of iron through aging may increase the potential for oxidative damage [11], which is exaggerated in the SNpc in PD [9]

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