Reduction of alpha-synuclein oligomers in preclinical models of Parkinson's disease by electrical stimulation in vitro and deep brain stimulation in vivo (2024)

Lee, E. J., Aguirre-Padilla, D. H., Fomenko, A., Pawar, G., Kapadia, M., George, J., Lozano, A. M., Hamani, C., Kalia, L. V., & Kalia, S. K. (2024). Reduction of alpha-synuclein oligomers in preclinical models of Parkinson's disease by electrical stimulation in vitro and deep brain stimulation in vivo. Brain stimulation, 17(2), 166-175. https://doi.org/10.1016/j.brs.2024.02.005

Lee, Eun Jung ; Aguirre-Padilla, David Hernán ; Fomenko, Anton et al. / Reduction of alpha-synuclein oligomers in preclinical models of Parkinson's disease by electrical stimulation in vitro and deep brain stimulation in vivo. In: Brain stimulation. 2024 ; Vol. 17, No. 2. pp. 166-175.

@article{306f39636c034ded8063484c197fd46c,

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

abstract = "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.",

keywords = "Alpha-synuclein, Deep brain stimulation, High frequency stimulation, Oligomers, Parkinson's disease, Substantia nigra, Subthalamic nucleus",

author = "Lee, {Eun Jung} and Aguirre-Padilla, {David Hern{\'a}n} and Anton Fomenko and Grishma Pawar and Minesh Kapadia and Jimmy George and Lozano, {Andres M.} and Clement Hamani and Kalia, {Lorraine V.} and Kalia, {Suneil K.}",

note = "Publisher Copyright: {\textcopyright} 2024 The Authors",

year = "2024",

month = mar,

doi = "10.1016/j.brs.2024.02.005",

language = "English",

volume = "17",

pages = "166--175",

journal = "Brain stimulation",

issn = "1935-861X",

publisher = "ELSEVIER SCIENCE INC",

number = "2",

}

Lee, EJ, Aguirre-Padilla, DH, Fomenko, A, Pawar, G, Kapadia, M, George, J, Lozano, AM, Hamani, C, Kalia, LV & Kalia, SK 2024, 'Reduction of alpha-synuclein oligomers in preclinical models of Parkinson's disease by electrical stimulation in vitro and deep brain stimulation in vivo', Brain stimulation, vol. 17, no. 2, pp. 166-175. https://doi.org/10.1016/j.brs.2024.02.005

Reduction of alpha-synuclein oligomers in preclinical models of Parkinson's disease by electrical stimulation in vitro and deep brain stimulation in vivo. / Lee, Eun Jung; Aguirre-Padilla, David Hernán; Fomenko, Anton et al.
In: Brain stimulation, Vol. 17, No. 2, 03.2024, p. 166-175.

Research output: Contribution to journal › Article › Academic › peer-review

TY - JOUR

T1 - Reduction of alpha-synuclein oligomers in preclinical models of Parkinson's disease by electrical stimulation in vitro and deep brain stimulation in vivo

AU - Lee, Eun Jung

AU - Aguirre-Padilla, David Hernán

AU - Fomenko, Anton

AU - Pawar, Grishma

AU - Kapadia, Minesh

AU - George, Jimmy

AU - Lozano, Andres M.

AU - Hamani, Clement

AU - Kalia, Lorraine V.

AU - Kalia, Suneil K.

N1 - Publisher Copyright:© 2024 The Authors

PY - 2024/3

Y1 - 2024/3

N2 - 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.

AB - 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.

KW - Alpha-synuclein

KW - Deep brain stimulation

KW - High frequency stimulation

KW - Oligomers

KW - Parkinson's disease

KW - Substantia nigra

KW - Subthalamic nucleus

UR - http://www.scopus.com/inward/record.url?scp=85185493044&partnerID=8YFLogxK

U2 - 10.1016/j.brs.2024.02.005

DO - 10.1016/j.brs.2024.02.005

M3 - Article

C2 - 38342364

AN - SCOPUS:85185493044

SN - 1935-861X

VL - 17

SP - 166

EP - 175

JO - Brain stimulation

JF - Brain stimulation

IS - 2

ER -

Lee EJ, Aguirre-Padilla DH, Fomenko A, Pawar G, Kapadia M, George J et al. Reduction of alpha-synuclein oligomers in preclinical models of Parkinson's disease by electrical stimulation in vitro and deep brain stimulation in vivo. Brain stimulation. 2024 Mar;17(2):166-175. doi: 10.1016/j.brs.2024.02.005