Long-Term Exposure to PFE-360 in the AAV-α-Synuclein Rat Model: Findings and Implications

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Long-Term Exposure to PFE-360 in the AAV-α-Synuclein Rat Model : Findings and Implications. / Andersen, Michael Aagaard; Sotty, Florence; Jensen, Poul Henning; Badolo, Lassina; Jeggo, Ross; Smith, Garrick Paul; Christensen, Kenneth Vielsted.

In: eNeuro, Vol. 6, No. 6, 07.11.2019.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Andersen, MA, Sotty, F, Jensen, PH, Badolo, L, Jeggo, R, Smith, GP & Christensen, KV 2019, 'Long-Term Exposure to PFE-360 in the AAV-α-Synuclein Rat Model: Findings and Implications', eNeuro, vol. 6, no. 6. https://doi.org/10.1523/ENEURO.0453-18.2019

APA

Andersen, M. A., Sotty, F., Jensen, P. H., Badolo, L., Jeggo, R., Smith, G. P., & Christensen, K. V. (2019). Long-Term Exposure to PFE-360 in the AAV-α-Synuclein Rat Model: Findings and Implications. eNeuro, 6(6). https://doi.org/10.1523/ENEURO.0453-18.2019

Vancouver

Andersen MA, Sotty F, Jensen PH, Badolo L, Jeggo R, Smith GP et al. Long-Term Exposure to PFE-360 in the AAV-α-Synuclein Rat Model: Findings and Implications. eNeuro. 2019 Nov 7;6(6). https://doi.org/10.1523/ENEURO.0453-18.2019

Author

Andersen, Michael Aagaard ; Sotty, Florence ; Jensen, Poul Henning ; Badolo, Lassina ; Jeggo, Ross ; Smith, Garrick Paul ; Christensen, Kenneth Vielsted. / Long-Term Exposure to PFE-360 in the AAV-α-Synuclein Rat Model : Findings and Implications. In: eNeuro. 2019 ; Vol. 6, No. 6.

Bibtex

@article{8c00d3f469c547d2811ca32e8a5cfcce,
title = "Long-Term Exposure to PFE-360 in the AAV-α-Synuclein Rat Model: Findings and Implications",
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 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.",
keywords = "Animals, Antiparkinson Agents/pharmacology, Corpus Striatum/drug effects, Dependovirus/genetics, Disease Models, Animal, Female, Genetic Vectors, Humans, Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/antagonists & inhibitors, Morpholines/pharmacology, Motor Activity/drug effects, Neurons/drug effects, Parkinson Disease/drug therapy, Protein Kinase Inhibitors/pharmacology, Pyrimidines/pharmacology, Pyrroles/pharmacology, Rats, Sprague-Dawley, Subthalamic Nucleus/drug effects, Time Factors, Tyrosine 3-Monooxygenase/metabolism, alpha-Synuclein/genetics",
author = "Andersen, {Michael Aagaard} and Florence Sotty and Jensen, {Poul Henning} and Lassina Badolo and Ross Jeggo and Smith, {Garrick Paul} and Christensen, {Kenneth Vielsted}",
note = "Copyright {\textcopyright} 2019 Andersen et al.",
year = "2019",
month = nov,
day = "7",
doi = "10.1523/ENEURO.0453-18.2019",
language = "English",
volume = "6",
journal = "eNeuro",
issn = "2373-2822",
publisher = "Society for Neuroscience",
number = "6",

}

RIS

TY - JOUR

T1 - Long-Term Exposure to PFE-360 in the AAV-α-Synuclein Rat Model

T2 - Findings and Implications

AU - Andersen, Michael Aagaard

AU - Sotty, Florence

AU - Jensen, Poul Henning

AU - Badolo, Lassina

AU - Jeggo, Ross

AU - Smith, Garrick Paul

AU - Christensen, Kenneth Vielsted

N1 - Copyright © 2019 Andersen et al.

PY - 2019/11/7

Y1 - 2019/11/7

N2 - 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 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.

AB - 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 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.

KW - Animals

KW - Antiparkinson Agents/pharmacology

KW - Corpus Striatum/drug effects

KW - Dependovirus/genetics

KW - Disease Models, Animal

KW - Female

KW - Genetic Vectors

KW - Humans

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

KW - Morpholines/pharmacology

KW - Motor Activity/drug effects

KW - Neurons/drug effects

KW - Parkinson Disease/drug therapy

KW - Protein Kinase Inhibitors/pharmacology

KW - Pyrimidines/pharmacology

KW - Pyrroles/pharmacology

KW - Rats, Sprague-Dawley

KW - Subthalamic Nucleus/drug effects

KW - Time Factors

KW - Tyrosine 3-Monooxygenase/metabolism

KW - alpha-Synuclein/genetics

U2 - 10.1523/ENEURO.0453-18.2019

DO - 10.1523/ENEURO.0453-18.2019

M3 - Journal article

C2 - 31685675

VL - 6

JO - eNeuro

JF - eNeuro

SN - 2373-2822

IS - 6

ER -

ID: 248024271