Nov 12, 2018

Long-term exposure to PFE-360 in the AAV-α-synuclein rat model: findings and implications

BioRxiv : the Preprint Server for Biology
Michael Aagaard AndersenKenneth Vielsted Christensen

Abstract

Parkinson's disease (PD) is a progressive neurodegenerative disorder associated with impaired motor function and several non-motor symptoms, with no available disease modifying treatment. Intracellular accumulation of pathological α-synuclein inclusions is a hallmark of idiopathic PD, whereas, dominant mutations in Leucine-rich repeat kinase 2 (LRRK2) are associated with familial PD that is clinically indistinguishable from idiopathic PD. Recent evidence supports the hypothesis that an increase in LRRK2 kinase activity is associated with the development of not only familial LRRK2 PD, but also idiopathic PD. Previous reports have shown preclinical effects of LRRK2 modulation on α-synuclein-induced neuropathology. Increased subthalamic nucleus (STN) burst firing in preclinical neurotoxin models and PD patients is hypothesized to be causally involved in the development of the motor deficit in PD. To study a potential pathophysiological relationship between α-synuclein pathology and LRRK2 kinase activity in PD, we investigated the effect of chronic LRRK2 inhibition in an AAV-α-synuclein overexpression rat model. In this study, we report that chronic LRRK2 inhibition using PFE-360 partially restores motor function. However, this eff...Continue Reading

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Mentioned in this Paper

Study
AAVS1
Neurotoxins
Protoplasm
SNCA wt Allele
Neuropathology
Perfluoroethylcyclohexane
Motor Function
Metabolic Inhibition
LRRK2

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