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

## TL;DR

This study shows that direct current stimulation can reduce harmful alpha-synuclein buildup in neurons linked to Parkinson's disease.

## Contribution

The study demonstrates that direct current stimulation reduces alpha-synuclein aggregation in primary neurons, a novel finding for Parkinson’s disease treatment.

## Key findings

- Direct current stimulation reduced both wild-type and A53T alpha-synuclein aggregation in neurons.
- DCS increased neuronal viability and promoted clearance of intracellular alpha-synuclein.
- Extracellular alpha-synuclein levels increased, suggesting enhanced neuronal activity and clearance.

## Abstract

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.

This study found neuromodulation, by direct current stimulation (DCS) applied to primary neurons, disrupted the aggregation of the Parkinson’s disease linked, misfolded α-synuclein protein. Indeed, DCS promoted intracellular alpha-synuclein clearance and increased neuronal survival. These findings support electrical neuromodulation as a means of reducing pathological α-synuclein load.

Graphical Abstract