L-DOPA regulates α-synuclein accumulation in experimental parkinsonism

Aims Widespread accumulation of misfolded alpha-synuclein aggregates is a key feature of Parkinson's disease (PD). Although the pattern and extent of alpha-synuclein accumulation through PD brains is known, the impact of chronic dopamine-replacement therapy (the gold-standard pharmacological treatment of PD) on the fate of alpha-synuclein is still unknown. Here, we investigated the distribution and accumulation of alpha-synuclein in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) non-human primate model of PD and determined the effect of chronic L-DOPA treatment on MPTP-induced alpha-synuclein pathology. Methods We measured the density of alpha-synuclein and tau immuno-positive neurons in the substantia nigra, putamen, hippocampal CA1 region, temporal cortex and dentate nucleus of control, MPTP and MPTP+L-DOPA-treated monkeys. Moreover, we also extracted and quantified Triton-X (TX) soluble and insoluble alpha-synuclein in putamen and hippocampus samples from a separate cohort of control, MPTP and MPTP+L-DOPA-treated monkeys. Results MPTP-induced alpha-synuclein accumulation in NHP model of PD was not limited to the substantia nigra but also occurred in the putamen, hippocampal CA1 region and temporal cortex. Tau was increased only in the temporal cortex. Moreover, increased intraneuronal TX insoluble alpha-synuclein was truncated, but not in the structural form of Lewy bodies. The MPTP-induced increase in alpha-synuclein levels was abolished in animals having received L-DOPA in all the brain regions, except in the substantia nigra. Conclusions Dopamine replacement therapy can dramatically ameliorate alpha-synuclein pathology in the MPTP NHP model of PD. Therefore, patient's dopaminergic medication should be systematically considered when assessing alpha-synuclein as a biomarker for diagnosis, monitoring disease progression and response to disease-modifying treatments.

Automated summary

The study found that chronic dopamine-replacement therapy can significantly ameliorate alpha-synuclein pathology in the non-human primate model of Parkinson's disease. Therefore, patient's dopaminergic medication should be systematically considered when assessing the disease.