The Compound ATH434 Prevents Alpha-Synuclein Toxicity in a Murine Model of Multiple System Atrophy

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.

Pathogenic Impact of α-Synuclein Phosphorylation and Its Kinases in α-Synucleinopathies

“…We recently showed that clearance of p-Ser129 α-synuclein alleviates cognitive and motor dysfunction in a Parkinson’s disease mouse model [ 50 ]. We also developed a therapeutic compound targeting metal ions, which has the potential to modulate α-synuclein metal binding and alleviate its accumulation [ 122 , 123 ]. Based on our finding that fatty-acid-binding proteins are critical for the accumulation of α-synuclein following phosphorylation [ 17 , 19 , 37 ], we intend to develop more fundamental therapeutics and diagnostic tools for α-synucleinopathies, including Parkinson’s disease, DLB, and multiple system atrophies.…”

Aberrant Cerebral Iron Trafficking Co-morbid With Chronic Inflammation: Molecular Mechanisms and Pharmacologic Intervention

“…Indeed, recent reports of the efficacy of a quinazolinone derivative, PBT434, in a Phase I trial involving Multiple System Atrophy indicate the potential of such chemical platforms ( 199 ). PBT434 suppresses α-synuclein toxicity in models of Parkinson's disease ( 200 ) and MSA ( 201 ). PBT434 has a moderate affinity for both ferrous and ferric iron (stability constants ~10 7 ); has a redox potential that supports cell anti-oxidant activity; and exhibits facile equilibration across the BBB without disrupting iron homeostasis in BMVEC ( 200 , 202 ).…”

Inhibition of Protein Aggregation and Endoplasmic Reticulum Stress as a Targeted Therapy for α-Synucleinopathy

“…The compound decreased α-syn aggregation, toxicity and activated DA receptors D2/D3 in animal models of PD [ 297 ]. PBT434 is a 8-hydroxyquinoline (8-HQ) derivative, which, apart from binding iron, was shown to decrease levels of oligomeric and fibrillar α-syn in murine models of MSA and PD [ 298 , 299 , 300 ]. The efficacy and safety of PBT434 were investigated in a phase I trial, in which the compound achieved a favorable and proportional pharmacokinetic profile, was non-toxic and well-tolerated [ 301 ].…”