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Neurobiol Dis. 2018 Aug;116:13-27. doi: 10.1016/j.nbd.2018.04.011. Epub 2018 Apr 20.

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

Author information

1
Department of Neurodegeneration, Neuroscience Drug Discovery DK, H. Lundbeck A/S, Valby, Denmark; Department of Biomedicine, Dandrite, Faculty of Health, Aarhus University, Aarhus, Denmark. Electronic address: aaga@lundbeck.com.
2
Department of Neurodegeneration, Neuroscience Drug Discovery DK, H. Lundbeck A/S, Valby, Denmark.
3
Department of Discovery DMPK, H. Lundbeck A/S, Valby, Denmark.
4
Department of Discovery Chemistry 2, H. Lundbeck A/S, Valby, Denmark.
5
Department of Biomedicine, Dandrite, Faculty of Health, Aarhus University, Aarhus, Denmark.

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.

KEYWORDS:

AAV-alpha-synuclein; In vivo electrophysiology; LRRK2 inhibition; LRRK2 inhibitor; PFE-360; Parkinson's disease; Single unit recording; Subthalamic nucleus; Subthalamic nucleus burst firing

PMID:
29680709
DOI:
10.1016/j.nbd.2018.04.011
[Indexed for MEDLINE]

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