Objective: To investigate the role of lipid metabolism and the effect of blocking carnitine palmitoyl-transferase 1 (CPT1) in toxic and genetically mouse models of Parkinson’s disease (PD).

Background: Parkinson’s disease is characterized as a neurodegenerative disease resulting in death of dopaminergic neurons. However, multiple studies indicate that dysregulation of metabolism is a hallmark in the pathogenesis. Studies indicate that lipid metabolism is upregulated and glucose metabolism downregulated resulting in disruption of homeostasis at the local and systemic level.

Method: Mice with a Cpt1a p479l mutation was generated in collaboration with Netherlands Cancer Institute. These mice and C57Bl/6J (B6) male mice were exposed to a chronic oral gavage rotenone regime (30mg/kg) for 32 days and evaluated for clinical symptoms of PD using motor and sensorimotor tests. Mice were euthanized and samples was collected at day 32. B6 male mice were exposed to rotenone (30mg/kg) for 32 days and assessed for clinical symptoms of PD using motor and sensorimotor tests and randomized into treatment with a CPT1-blocker or placebo for 30 days. Treatment with CPT1-blocker or placebo alternated with rotenone administration resulting in a total of 18 days of CPT1-blocker or placebo treatment. At day 56 and 60 mice were evaluated for clinical symptoms of PD. Mice were euthanized and samples was harvested at day 62. Microbiota analysis was performed on fecal samples from the Cpt1a p479l and CPT1-blocker experiment using 16s RNA sequencing. B6.129S4-Prkntm1Shn/J mice (PARK2) were bought from Jackson, USA and bred in at Aalborg University animal facility. Male PARK2 and B6 mice were assessed for clinical symptoms of PD and randomized into treatment with a CPT1-blocker or placebo for 4 weeks.

Results: Mice with a Cpt1a p479l mutation showed resistant against rotenone induced PD and performed significant better compared to wildtype mice at day 32. B6 mice developed clinical symptoms of PD following 32 days of rotenone administration. CPT1-blocker was able to reverse clinical symptoms of PD at day 56 and 60. Microbiota analysis revealed several significant differences between treatment groups and genotypes (Cpt1a p479L and B6). Results from the PARK2 experiment are pending and will be presented at the conference.

Conclusion: CPT1 and CPT1a is emerging as a promising target for the treatment of PD.

« Back to 2019 International Congress

MDS Abstracts - https://www.mdsabstracts.org/abstract/the-role-of-lipid-metabolism-in-mouse-models-of-parkinsons-disease/