Poul Henning Jensen

Parkinson's disease-like burst firing activity in subthalamic nucleus induced by AAV-α-synuclein is normalized by LRRK2 modulation

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

Standard

Parkinson's disease-like burst firing activity in subthalamic nucleus induced by AAV-α-synuclein is normalized by LRRK2 modulation. / Andersen, Michael Aagaard; Christensen, Kenneth Vielsted; Badolo, Lassina; Smith, Garrick Paul; Jeggo, Ross; Jensen, Poul Henning; Andersen, Kathrine Just; Sotty, Florence.

In: Neurobiology of Disease, Vol. 116, 08.2018, p. 13-27.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

Harvard

Andersen, MA, Christensen, KV, Badolo, L, Smith, GP, Jeggo, R, Jensen, PH, Andersen, KJ & Sotty, F 2018, 'Parkinson's disease-like burst firing activity in subthalamic nucleus induced by AAV-α-synuclein is normalized by LRRK2 modulation', Neurobiology of Disease, vol. 116, pp. 13-27. https://doi.org/10.1016/j.nbd.2018.04.011

APA

Andersen, M. A., Christensen, K. V., Badolo, L., Smith, G. P., Jeggo, R., Jensen, P. H., Andersen, K. J., & Sotty, F. (2018). Parkinson's disease-like burst firing activity in subthalamic nucleus induced by AAV-α-synuclein is normalized by LRRK2 modulation. Neurobiology of Disease, 116, 13-27. https://doi.org/10.1016/j.nbd.2018.04.011

CBE

Andersen MA, Christensen KV, Badolo L, Smith GP, Jeggo R, Jensen PH, Andersen KJ, Sotty F. 2018. Parkinson's disease-like burst firing activity in subthalamic nucleus induced by AAV-α-synuclein is normalized by LRRK2 modulation. Neurobiology of Disease. 116:13-27. https://doi.org/10.1016/j.nbd.2018.04.011

MLA

Vancouver

Author

Andersen, Michael Aagaard ; Christensen, Kenneth Vielsted ; Badolo, Lassina ; Smith, Garrick Paul ; Jeggo, Ross ; Jensen, Poul Henning ; Andersen, Kathrine Just ; Sotty, Florence. / Parkinson's disease-like burst firing activity in subthalamic nucleus induced by AAV-α-synuclein is normalized by LRRK2 modulation. In: Neurobiology of Disease. 2018 ; Vol. 116. pp. 13-27.

Bibtex

@article{e493f56aab764559bb9d31339c3bf507,
title = "Parkinson's disease-like burst firing activity in subthalamic nucleus induced by AAV-α-synuclein is normalized by LRRK2 modulation",
abstract = "Parkinson's disease (PD) affects motor function through degenerative processes and synaptic transmission impairments in the basal ganglia. None of the treatments available delays or stops the progression of the disease. While α-synuclein pathological accumulation represents a hallmark of the disease in its idiopathic form, leucine rich repeat kinase 2 (LRRK2) is genetically associated with familial and sporadic forms of PD. The genetic information suggests that LRRK2 kinase activity plays a role in the pathogenesis of the disease. To support a potential link between LRRK2 and α-synuclein in the pathophysiological mechanisms underlying PD, the effect of LRRK2 ablation or LRRK2 kinase pharmacological inhibition were studied in rats with adeno-associated virus-induced (AAV) α-synuclein overexpression in the nigrostriatal pathway. We first report that viral overexpression of α-synuclein induced increased burst firing in subthalamic neurons. Aberrant firing pattern of subthalamic neurons has also been reported in PD patients and neurotoxin-based animal models, and is hypothesized to play a key role in the appearance of motor dysfunction. We further report that genetic LRRK2 ablation, as well as pharmacological inhibition of LRRK2 kinase activity with PFE-360, reversed the aberrant firing pattern of subthalamic neurons induced by AAV-α-synuclein overexpression. This effect of LRRK2 modulation was not associated with any neuroprotective effect or motor improvement. Nonetheless, our findings may indicate a potential therapeutic benefit of LRRK2 kinase inhibition by normalizing the aberrant neuronal activity of subthalamic neurons induced by AAV-α-synuclein, a neurophysiological trait recapitulating observations in PD.",
author = "Andersen, {Michael Aagaard} and Christensen, {Kenneth Vielsted} and Lassina Badolo and Smith, {Garrick Paul} and Ross Jeggo and Jensen, {Poul Henning} and Andersen, {Kathrine Just} and Florence Sotty",
note = "Copyright {\textcopyright} 2018 Elsevier Inc. All rights reserved.",
year = "2018",
month = aug,
doi = "10.1016/j.nbd.2018.04.011",
language = "English",
volume = "116",
pages = "13--27",
journal = "Neurobiology of Disease",
issn = "0969-9961",
publisher = "Academic Press",

}

RIS

TY - JOUR

T1 - Parkinson's disease-like burst firing activity in subthalamic nucleus induced by AAV-α-synuclein is normalized by LRRK2 modulation

AU - Andersen, Michael Aagaard

AU - Christensen, Kenneth Vielsted

AU - Badolo, Lassina

AU - Smith, Garrick Paul

AU - Jeggo, Ross

AU - Jensen, Poul Henning

AU - Andersen, Kathrine Just

AU - Sotty, Florence

N1 - Copyright © 2018 Elsevier Inc. All rights reserved.

PY - 2018/8

Y1 - 2018/8

N2 - Parkinson's disease (PD) affects motor function through degenerative processes and synaptic transmission impairments in the basal ganglia. None of the treatments available delays or stops the progression of the disease. While α-synuclein pathological accumulation represents a hallmark of the disease in its idiopathic form, leucine rich repeat kinase 2 (LRRK2) is genetically associated with familial and sporadic forms of PD. The genetic information suggests that LRRK2 kinase activity plays a role in the pathogenesis of the disease. To support a potential link between LRRK2 and α-synuclein in the pathophysiological mechanisms underlying PD, the effect of LRRK2 ablation or LRRK2 kinase pharmacological inhibition were studied in rats with adeno-associated virus-induced (AAV) α-synuclein overexpression in the nigrostriatal pathway. We first report that viral overexpression of α-synuclein induced increased burst firing in subthalamic neurons. Aberrant firing pattern of subthalamic neurons has also been reported in PD patients and neurotoxin-based animal models, and is hypothesized to play a key role in the appearance of motor dysfunction. We further report that genetic LRRK2 ablation, as well as pharmacological inhibition of LRRK2 kinase activity with PFE-360, reversed the aberrant firing pattern of subthalamic neurons induced by AAV-α-synuclein overexpression. This effect of LRRK2 modulation was not associated with any neuroprotective effect or motor improvement. Nonetheless, our findings may indicate a potential therapeutic benefit of LRRK2 kinase inhibition by normalizing the aberrant neuronal activity of subthalamic neurons induced by AAV-α-synuclein, a neurophysiological trait recapitulating observations in PD.

AB - Parkinson's disease (PD) affects motor function through degenerative processes and synaptic transmission impairments in the basal ganglia. None of the treatments available delays or stops the progression of the disease. While α-synuclein pathological accumulation represents a hallmark of the disease in its idiopathic form, leucine rich repeat kinase 2 (LRRK2) is genetically associated with familial and sporadic forms of PD. The genetic information suggests that LRRK2 kinase activity plays a role in the pathogenesis of the disease. To support a potential link between LRRK2 and α-synuclein in the pathophysiological mechanisms underlying PD, the effect of LRRK2 ablation or LRRK2 kinase pharmacological inhibition were studied in rats with adeno-associated virus-induced (AAV) α-synuclein overexpression in the nigrostriatal pathway. We first report that viral overexpression of α-synuclein induced increased burst firing in subthalamic neurons. Aberrant firing pattern of subthalamic neurons has also been reported in PD patients and neurotoxin-based animal models, and is hypothesized to play a key role in the appearance of motor dysfunction. We further report that genetic LRRK2 ablation, as well as pharmacological inhibition of LRRK2 kinase activity with PFE-360, reversed the aberrant firing pattern of subthalamic neurons induced by AAV-α-synuclein overexpression. This effect of LRRK2 modulation was not associated with any neuroprotective effect or motor improvement. Nonetheless, our findings may indicate a potential therapeutic benefit of LRRK2 kinase inhibition by normalizing the aberrant neuronal activity of subthalamic neurons induced by AAV-α-synuclein, a neurophysiological trait recapitulating observations in PD.

U2 - 10.1016/j.nbd.2018.04.011

DO - 10.1016/j.nbd.2018.04.011

M3 - Journal article

C2 - 29680709

VL - 116

SP - 13

EP - 27

JO - Neurobiology of Disease

JF - Neurobiology of Disease

SN - 0969-9961

ER -