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

Eun Jung Lee; David Hernán Aguirre-Padilla; Anton Fomenko; Grishma Pawar; Minesh Kapadia; Jimmy George; Andres M. Lozano; Clement Hamani; Lorraine V. Kalia; Suneil K. Kalia

Brain Stimulation (Mar 2024)

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

Eun Jung Lee,
David Hernán Aguirre-Padilla,
Anton Fomenko,
Grishma Pawar,
Minesh Kapadia,
Jimmy George,
Andres M. Lozano,
Clement Hamani,
Lorraine V. Kalia,
Suneil K. Kalia

Affiliations

Eun Jung Lee: Krembil Research Institute, Toronto Western Hospital, University Health Network, Toronto, ON, Canada; Department of Neurosurgery, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea
David Hernán Aguirre-Padilla: Krembil Research Institute, Toronto Western Hospital, University Health Network, Toronto, ON, Canada; Neuromodulation and Functional Neurosurgery Program, San Borja Arriarán Hospital, Santiago, Chile; Department of Neurology and Neurosurgery, Medical School, University of Chile, Santiago, Chile; Department of Biomedical Engineering, University Medical Center Groningen, Groningen University, Groningen, Netherlands
Anton Fomenko: Krembil Research Institute, Toronto Western Hospital, University Health Network, Toronto, ON, Canada; Division of Neurosurgery, Department of Surgery, University of Toronto, Toronto, ON, Canada
Grishma Pawar: Krembil Research Institute, Toronto Western Hospital, University Health Network, Toronto, ON, Canada
Minesh Kapadia: Krembil Research Institute, Toronto Western Hospital, University Health Network, Toronto, ON, Canada
Jimmy George: Krembil Research Institute, Toronto Western Hospital, University Health Network, Toronto, ON, Canada
Andres M. Lozano: Krembil Research Institute, Toronto Western Hospital, University Health Network, Toronto, ON, Canada; Division of Neurosurgery, Department of Surgery, University of Toronto, Toronto, ON, Canada; CenteR for Advancing Neurotechnological Innovation to Application (CRANIA), Toronto, Ontario, Canada
Clement Hamani: Division of Neurosurgery, Department of Surgery, University of Toronto, Toronto, ON, Canada; Sunnybrook Research Institute, Hurvitz Brain Sciences Centre, Toronto, ON, Canada
Lorraine V. Kalia: Krembil Research Institute, Toronto Western Hospital, University Health Network, Toronto, ON, Canada; Division of Neurology, Department of Medicine, University of Toronto, Toronto, ON, Canada; Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, ON, Canada
Suneil K. Kalia: Krembil Research Institute, Toronto Western Hospital, University Health Network, Toronto, ON, Canada; Division of Neurosurgery, Department of Surgery, University of Toronto, Toronto, ON, Canada; CenteR for Advancing Neurotechnological Innovation to Application (CRANIA), Toronto, Ontario, Canada; Corresponding author. Krembil Research Institute, Toronto Western Hospital, University Health Network, Toronto, ON, Canada.

Journal volume & issue: Vol. 17, no. 2
pp. 166 – 175

Abstract

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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 (α-Syn) are implicated in the loss of dopaminergic neurons in the substantia nigra in PD, making α-Syn a potential therapeutic target for disease modification. Objective: We examined the effects of high frequency electrical stimulation on α-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 α-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 α-Syn oligomers. Results: High frequency electrical stimulation reduced the expression of PD-associated mutant α-Syn and mitigated α-Syn oligomerization in cultured neurons. Furthermore, DBS in the substantia nigra, but not the subthalamic nucleus, decreased overall levels of α-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 α-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.

Published in Brain Stimulation

ISSN: 1935-861X (Print); 1876-4754 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Medicine: Internal medicine: Neurosciences. Biological psychiatry. Neuropsychiatry
Website: https://www.journals.elsevier.com/brain-stimulation

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