Prolyl Endopeptidase modulation by ACT-02 prevents a-synuclein aggregation in a transgenic model of Parkinson disease
ACT-02 modulates alpha-synuclein (a-syn) aggregation, and mitochondria dysfunction. associated with Prolyl Endopeptidase (PREP) activity. ACT-02 is a highly
selective and potent PREP inhibitor. We assessed ACT-02 in vivo efficacy in the Line 61 transgenic (Tg) mouse model overexpressing human α-synuclein under the Thy1
promoter.
A total of 64 male Tg Line 61 mice 1.5 months old, and 16 non-transgenic age- and sex-matched littermates were randomly allocated to 5 groups of 16 animals per
group. All animals received daily gavage administration of ACT-02 at three different doses (1, 5 and 10 mg/kg) or vehicle (n=16 animals/group) for a period of 13 weeks.
At the end of treatment, protein was extracted from the cortex, hippocampus, and striatum from all groups (5 groups, 40 animals in total). Human a-syn aggregation
and complex I activity were determined in the cortex, hippocampus, and striatum of all animals.
We observed a significant decrease on a-syn aggregation in the cortex in Tg mice treated with ACT-02 10 mg/kg compared to placebo (p=0.0207). Regarding complex I
activity in the cortex, treatment with 10 mg/kg restored complex I activity compared to vehicle-treatment. No statistical differences were detected in the hippocampus
and striatum between all groups compared to Tg control animals.
PREP modulation by ACT-02 improves PD neurodegeneration via multiple mechanisms in the Line 61 a-syn transgenic model, and therefore has potential therapeutic
value for disease modifying treatment of PD.
