Affiliations: [a] Florey Institute of Neuroscience and Mental Health and the University of Melbourne, Parkville, Victoria, Australia
| [b] Laboratory for Translational Neurodegeneration Research, Division of Neurobiology, Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria
Correspondence to: Professor David I. Finkelstein, Florey Institute of Neuroscience and Mental Health, 30 Royal Parade, Parkville, Victoria 3010, Australia. Tel.: +61 3 9035 6680; E-mail: [email protected].
Abstract: Background:An elevation in iron levels, together with an accumulation of α-synuclein within the oligodendrocytes, are features of the rare atypical parkinsonian disorder, Multiple System Atrophy (MSA). We have previously tested the novel compound ATH434 (formally called PBT434) in preclinical models of Parkinson’s disease and shown that it is brain-penetrant, reduces iron accumulation and iron-mediated redox activity, provides neuroprotection, inhibits alpha synuclein aggregation and lowers the tissue levels of alpha synuclein. The compound was also well-tolerated in a first-in-human oral dosing study in healthy and older volunteers with a favorable, dose-dependent pharmacokinetic profile. Objective:To evaluate the efficacy of ATH434 in a mouse MSA model. Methods:The PLP-α-syn transgenic mouse overexpresses α-synuclein, demonstrates oligodendroglial pathology, and manifests motor and non-motor aspects of MSA. Animals were provided ATH434 (3, 10, or 30 mg/kg/day spiked into their food) or control food for 4 months starting at 12 months of age and were culled at 16 months. Western blot was used to assess oligomeric and urea soluble α-synuclein levels in brain homogenates, whilst stereology was used to quantitate the number of nigral neurons and glial cell inclusions (GCIs) present in the substantia nigra pars compacta. Results:ATH434 reduced oligomeric and urea soluble α-synuclein aggregation, reduced the number of GCIs, and preserved SNpc neurons. In vitro experiments suggest that ATH434 prevents the formation of toxic oligomeric “species of synuclein”. Conclusion:ATH434 is a promising small molecule drug candidate that has potential to move forward to trial for treating MSA.
Keywords: Synuclein, iron, parkinsonism, neuroprotection, drug development