Abstract Details

Title PBT434 Prevents a-synuclein Aggregation, Neuron Loss, Motor Dysfunction and Reduces Glial Cell Inclusions in a Transgenic Mouse Model of Multiple System Atrophy

Topic Movement Disorders

Presentation(s) P5 - Poster Session 5 (5:30 PM-6:30 PM)

Poster/Presentation
Number 10-006

Objective To evaluate the efficacy of PBT434 in a mouse model of multiple system atrophy (MSA)

Background PBT434 is a novel, brain-penetrant, small molecule inhibitor of α-synuclein aggregation. In several animal models of Parkinson disease, PBT434 reduced α-synuclein aggregation and oxidative stress, preserved neurons and improved motor function (doi:10.1186/s40478-017-0456-2). The PLP-α-Syn transgenic model overexpresses α-synuclein, demonstrates oligodendroglial pathology and manifests motor and non-motor aspects of MSA (doi:10.1016/j.expneurol.2010.05.008). PBT434 is thought to act by redistributing reactive iron across membranes, thereby blocking intracellular protein aggregation and oxidative stress. The affinity of PBT434 for iron is greater than that of α-synuclein but lower than that of iron trafficking proteins, e.g., ferritin.

Design/Methods PBT434 or vehicle was administered orally for 4 (±1) months at 3 to 30 mg/kg/day starting at age 8 or 12 months. Mice were culled at 12 or 16 months. Western blots assessed oligomeric and aggregated α-synuclein brain levels. Nigral neuron counts (12 and 16 months) and glial cell inclusions (GCI) were assessed in the substantia nigra (SN) and pons (16 months) by stereology. Motor function was assessed with the pole test at 12 and 16 months.

Results At 12 and 16 months, PBT434 reduced oligomeric (P<0.05 and P<0.01) and aggregated (P<0.05 and P<0.01) α-synuclein, respectively, and preserved SN neurons at 16 months (P<0.001). At 16 months, PBT434 reduced GCI in SN and pons (P<0.001 and P<0.01, respectively). PBT434 improved motor function on the pole test at 12 and 16 months (P<0.05).

Conclusions PBT434 reduced α-synuclein aggregation and glial cell inclusions, preserved SN neurons and improved motor function in an animal model of MSA. PBT434 is a small molecule drug candidate with potential for treating MSA.

Authors/Disclosures
David T. Finkelstein, MD (Ennoble Care) PRESENTER	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
David A. Stamler, MD (Alterity Therapeutics)	Dr. Stamler has received personal compensation for serving as an employee of Alterity Therapeutics. Dr. Stamler has stock in Alterity Therapeutics.

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