Direct current stimulation induced reduction in α-synuclein in primary neurons: targeting Parkinson's disease

Targeted electrical approaches to the treatment for Parkinson's disease include deep brain stimulation, which is effective for core motor symptoms, such as essential tremor. Interestingly, treating comorbid depressive symptoms in Parkinson's disease, using electroconvulsive therapy, also appears to help motor disability. But it is unclear whether such electrical strategies have any impact on the underlying disease processes of Parkinson's disease. Since aggregation of misfolded alpha-synuclein fibrils is a pathological hallmark of Parkinson's disease, this may be an important therapeutic target. To this end, we presently assessed whether direct current stimulation (DCS) of cortical neurons that were seeded with wild-type or A53T alpha-synuclein mutant pre-formed fibrils (PFFs) would reduce their aggregation. We found that both wild-type and A53T alpha-synuclein PFFs readily induced alpha-synuclein aggregation in primary cortical neurons and this effect was more pronounced at embryonic Day 17 (E17), compared to less mature E14-derived neurons. We did find that DCS time dependently reduced alpha-synuclein accumulation (phosphorylated and aggregate forms) within neurons and increased neuronal viability. Increased extracellular alpha-synuclein levels suggest that the DCS induced an increase in neuronal activity causing the clearance of the intracellular alpha-synuclein. These data have implications for non-invasive neuromodulation strategies to lower alpha-synuclein burden and possibly correct aberrant neuronal firing in Parkinson's disease and other alpha-synucleinopathies.