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.

KW - Action Potentials/drug effects

KW - Animals

KW - Dependovirus/genetics

KW - Female

KW - Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/antagonists & inhibitors

KW - Parkinsonian Disorders/genetics

KW - Rats

KW - Rats, Long-Evans

KW - Rats, Sprague-Dawley

KW - Rats, Transgenic

KW - Subthalamic Nucleus/drug effects

KW - alpha-Synuclein/biosynthesis

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 -