@article {AndersenENEURO.0453-18.2019, author = {Michael Aagaard Andersen and Florence Sotty and Poul Henning Jensen and Lassina Badolo and Ross Jeggo and Garrick Paul Smith and Kenneth Vielsted Christensen}, title = {Long-term exposure to PFE-360 in the AAV-α-synuclein rat model: findings and implications}, elocation-id = {ENEURO.0453-18.2019}, year = {2019}, doi = {10.1523/ENEURO.0453-18.2019}, publisher = {Society for Neuroscience}, abstract = {Parkinson{\textquoteright}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 only induced a marginal effect on motor function. In addition, the aberrant STN burst firing and associated neurodegenerative processes induced by α-synuclein overexpression model remained unaffected by chronic LRRK2 inhibition. Our findings do not strongly support LRRK2 inhibition for the treatment of PD. Therefore, the reported beneficial effects of LRRK2 inhibition in similar α-synuclein overexpression rodent models must be considered with prudence and additional studies are warranted in alternative α-synuclein-based models.Significance statement Mutations in LRRK2 and α-synuclein are known risk factors for Parkinson{\textquoteright}s disease. α-synuclein aggregates at autopsies in both idiopathic and most G2019S cases is suggestive of a common disease pathogenesis. LRRK2 and α-synuclein interaction is hypothesized to play a pivotal role in the pathological mechanisms. Preclinical in vivo evidence of a beneficial effect of LRRK2 inhibition is mixed and limited. This study increases our understanding but underlines the complexity of LRRK2 as a mediator of neuronal dysfunction; importantly, the present findings further outline some of the limitations inherent to the PD model used, and warrant additional preclinical studies in animal models with better relevance to the clinical pathophysiology to draw conclusion on the therapeutic potential of LRRK2 modulation in PD.}, URL = {https://www.eneuro.org/content/early/2019/11/04/ENEURO.0453-18.2019}, eprint = {https://www.eneuro.org/content/early/2019/11/04/ENEURO.0453-18.2019.full.pdf}, journal = {eNeuro} }