Reduction of alpha-synuclein oligomers in preclinical models of Parkinson's disease by electrical stimulation in vitro and deep brain stimulation in vivo

Background: Deep brain stimulation (DBS) has been widely used to manage debilitating neurological symptoms in movement disorders such as Parkinson's disease (PD). Despite its well-established symptomatic benefits, our understanding of the mechanisms underlying DBS and its possible effect on the accumulation of pathological proteins in neurodegeneration remains limited. Accumulation and oligomerization of the protein alpha-synuclein (alpha-Syn) are implicated in the loss of dopaminergic neurons in the substantia nigra in PD, making alpha-Syn a potential therapeutic target for disease modification. Objective: We examined the effects of high frequency electrical stimulation on alpha-Syn levels and oligomerization in cell and rodent models. Methods: High frequency stimulation, mimicking DBS parameters used for PD, was combined with viral-mediated overexpression of alpha-Syn in cultured rat primary cortical neurons or in substantia nigra of rats. Bimolecular protein complementation with split fluorescent protein reporters was used to detect and quantify alpha-Syn oligomers. Results: High frequency electrical stimulation reduced the expression of PD-associated mutant alpha-Syn and mitigated alpha-Syn oligomerization in cultured neurons. Furthermore, DBS in the substantia nigra, but not the subthalamic nucleus, decreased overall levels of alpha-Syn, including oligomer levels, in the substantia nigra. Conclusions: Taken together, our results demonstrate that direct high frequency stimulation can reduce accumulation and pathological forms of alpha-Syn in cultured neurons in vitro and in substantia nigra in vivo. Thus, DBS therapy could have a role beyond symptomatic treatment, with potential disease-modifying properties that can be exploited to target pathological proteins in neurodegenerative diseases.