ATH434 Reduces α‐Synuclein‐Related Neurodegeneration in a Murine Model of Multiple System Atrophy

Abstract

A BS TRACT: Background: Multiple system atrophy (MSA) is a fatal neurodegenerative disorder characterized by aggregated α-synuclein (α-syn) in oligodendrocytes and accompanied by striatonigral and olivopontocerebellar degeneration and motor symptoms. Key features of MSA are replicated in the PLP-α-syn transgenic mouse, including progressive striatonigral degeneration and motor deterioration. There are currently no approved treatments for MSA. ATH434 is a novel, orally bioavailable brain penetrant small molecule inhibitor of α-syn aggregation. Objectives: To characterize ATH434 for disease modification in a mouse model of MSA. Methods: Six-month-old PLP-α-syn mice (MSA mice) were ATH434-treated (ATH434 in food) or untreated (normal food) for 6 months. Motor behavior and numbers of nigral and striatal neurons were evaluated. α-syn aggregates and oligomers were quantified by immunohistochemical and western blot analyses. Microglial activation and neuroinflammation were assessed by histological and molecular analyses. Ferric iron in the Substantia nigra was evaluated with the Perls method.Results: ATH434-treated mice demonstrated preservation of motor performance in MSA mice that was associated with neuroprotection of nigral and striatal neurons. The rescue of the phenotype correlated with the reduction of α-syn inclusions and oligomers in animals receiving ATH434. ATH434-treated mice exhibited significantly increased lysosomal activity of microglia without increased pro-inflammatory markers, suggesting a role in α-syn clearing. ATH434-treatment was associated with lower intracellular nigral iron levels. Conclusions: Our findings demonstrate the beneficial disease-modifying effect of ATH434 in oligodendroglial α-synucleinopathy on both the motor phenotype and neurodegenerative pathology in the PLP-α-syn transgenic mouse and support the development of ATH434 for MSA.

A Mouse Model of Multiple System Atrophy: Bench to Bedside

“…(3) multiple autonomic centers in the brain and spinal cord of PLP-a-syn mice show selective neuronal loss [87][88][89][90]; (4) nigral and striatal neuronal loss feature the underlying motor pathology in PLP-a-syn mice [78]; (5) olivopontocerebellar pathology can be triggered by mitochondrial or proteolytic stress in the PLP-a-syn mouse [85,86]; (6)(7)(8) the neurodegeneration is mediated through gliosis and neuroinflammatory signaling [18,85,112]; (9) early signs of oligodendroglial and myelin dysfunction [95] are accelerated by proteolytic stress [86]; and (10) iron deposition in the degenerating areas can be identified [102,105]. Created with BioRe nder.…”

“…All relevant current MSA models are based on the assumption that pathological a-syn is the cause of MSA neurodegeneration. On one hand, such a-syn models of MSA are advantageous when testing a-syn targeting treatment strategies, because they provide a clear-cut readout of efficacy based on a-syn pathology modulation [98][99][100][101][102][103][104][105]. Furthermore, the a-syn-based models of MSA provide the possibility to screen targeting of other relevant pathways and disease mechanisms downstream of a-syn pathology like neuroinflammation [18,19,78,106,107], neurotrophic disbalance [108,109], epigenetic impairment [110], or demyelination [97].…”

Disease-Modifying Therapies for Multiple System Atrophy: Where Are We in 2022?

“…First experiments with novel quinazolinone inhibitor ATH434 (previously known as PBT434) revealed reduced levels of ␣-synuclein and markers of oxidative stress accompanied by motor improvement in PD animal models [69]. Similar results were reproduced in transgenic MSA mice [70,71]. In a phase I study with healthy volunteers, ATH434 was safe and well tolerated (U1111-1211-0052) and achieved CSF concentrations comparable with those associated with efficacy in animal models [72,73].…”

Multiple system atrophy: α-Synuclein strains at the neuron-oligodendrocyte crossroad

“…Anle138b and ATH434 are two compounds tested in an MSA mouse model showing a reduction in protein oligomerization and an improvement of motor symptoms. Phase I clinical trials confirmed the safety of both compounds (Anle138b: NCT04208152), with a phase II trial in MSA patients being prepared to test Anle138b [ 166 – 168 ]. Immunotherapy is another approach being trialed in MSA and PD patients.…”