Inhibition of LRRK2 kinase activity rescues deficits in striatal dopamine physiology in VPS35 p.D620N knock-in mice
Abstract Dysregulation of dopamine neurotransmission profoundly affects motor, motivation and learning behaviors, and can be observed during the prodromal phase of Parkinson’s disease (PD). However, the mechanism underlying these pathophysiological changes remains to be elucidated. Mutations in vacu...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2023-12-01
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| Series: | npj Parkinson's Disease |
| Online Access: | https://doi.org/10.1038/s41531-023-00609-7 |
| _version_ | 1797377165299286016 |
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| author | Mengfei Bu Jordan Follett Isaac Deng Igor Tatarnikov Shannon Wall Dylan Guenther Melissa Maczis Genevieve Wimsatt Austen Milnerwood Mark S. Moehle Habibeh Khoshbouei Matthew J. Farrer |
| author_facet | Mengfei Bu Jordan Follett Isaac Deng Igor Tatarnikov Shannon Wall Dylan Guenther Melissa Maczis Genevieve Wimsatt Austen Milnerwood Mark S. Moehle Habibeh Khoshbouei Matthew J. Farrer |
| author_sort | Mengfei Bu |
| collection | DOAJ |
| description | Abstract Dysregulation of dopamine neurotransmission profoundly affects motor, motivation and learning behaviors, and can be observed during the prodromal phase of Parkinson’s disease (PD). However, the mechanism underlying these pathophysiological changes remains to be elucidated. Mutations in vacuolar protein sorting 35 (VPS35) and leucine-rich repeat kinase 2 (LRRK2) both lead to autosomal dominant PD, and VPS35 and LRRK2 may physically interact to govern the trafficking of synaptic cargos within the endo-lysosomal network in a kinase-dependent manner. To better understand the functional role of VPS35 and LRRK2 on dopamine physiology, we examined Vps35 haploinsufficient (Haplo) and Vps35 p.D620N knock-in (VKI) mice and how their behavior, dopamine kinetics and biochemistry are influenced by LRRK2 kinase inhibitors. We found Vps35 p.D620N significantly elevates LRRK2-mediated phosphorylation of Rab10, Rab12 and Rab29. In contrast, Vps35 haploinsufficiency reduces phosphorylation of Rab12. While striatal dopamine transporter (DAT) expression and function is similarly impaired in both VKI and Haplo mice, that physiology is normalized in VKI by treatment with the LRRK2 kinase inhibitor, MLi-2. As a corollary, VKI animals show a significant increase in amphetamine induced hyperlocomotion, compared to Haplo mice, that is also abolished by MLi-2. Taken together, these data show Vps35 p.D620N confers a gain-of-function with respect to LRRK2 kinase activity, and that VPS35 and LRRK2 functionally interact to regulate DAT function and striatal dopamine transmission. |
| first_indexed | 2024-03-08T19:48:47Z |
| format | Article |
| id | doaj.art-d7d5c549172147a4a35bf5c5e9f93f2c |
| institution | Directory Open Access Journal |
| issn | 2373-8057 |
| language | English |
| last_indexed | 2024-03-08T19:48:47Z |
| publishDate | 2023-12-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | npj Parkinson's Disease |
| spelling | doaj.art-d7d5c549172147a4a35bf5c5e9f93f2c2023-12-24T12:12:39ZengNature Portfolionpj Parkinson's Disease2373-80572023-12-019111210.1038/s41531-023-00609-7Inhibition of LRRK2 kinase activity rescues deficits in striatal dopamine physiology in VPS35 p.D620N knock-in miceMengfei Bu0Jordan Follett1Isaac Deng2Igor Tatarnikov3Shannon Wall4Dylan Guenther5Melissa Maczis6Genevieve Wimsatt7Austen Milnerwood8Mark S. Moehle9Habibeh Khoshbouei10Matthew J. Farrer11Department of Neurology, University of FloridaDepartment of Neurology, University of FloridaDepartment of Neurology, University of FloridaDjavad Mowafaghian Centre for Brain Health, University of British ColumbiaDepartment of Neurology, University of FloridaDepartment of Neurology, University of FloridaDepartment of Neurology, University of FloridaDepartment of Neurology, University of FloridaDepartment of Neurology & Neurosurgery, Montreal Neurological Institute, McGill UniversityDepartment of Pharmacology and Therapeutics, University of FloridaMcKnight Brain Institute, University of FloridaDepartment of Neurology, University of FloridaAbstract Dysregulation of dopamine neurotransmission profoundly affects motor, motivation and learning behaviors, and can be observed during the prodromal phase of Parkinson’s disease (PD). However, the mechanism underlying these pathophysiological changes remains to be elucidated. Mutations in vacuolar protein sorting 35 (VPS35) and leucine-rich repeat kinase 2 (LRRK2) both lead to autosomal dominant PD, and VPS35 and LRRK2 may physically interact to govern the trafficking of synaptic cargos within the endo-lysosomal network in a kinase-dependent manner. To better understand the functional role of VPS35 and LRRK2 on dopamine physiology, we examined Vps35 haploinsufficient (Haplo) and Vps35 p.D620N knock-in (VKI) mice and how their behavior, dopamine kinetics and biochemistry are influenced by LRRK2 kinase inhibitors. We found Vps35 p.D620N significantly elevates LRRK2-mediated phosphorylation of Rab10, Rab12 and Rab29. In contrast, Vps35 haploinsufficiency reduces phosphorylation of Rab12. While striatal dopamine transporter (DAT) expression and function is similarly impaired in both VKI and Haplo mice, that physiology is normalized in VKI by treatment with the LRRK2 kinase inhibitor, MLi-2. As a corollary, VKI animals show a significant increase in amphetamine induced hyperlocomotion, compared to Haplo mice, that is also abolished by MLi-2. Taken together, these data show Vps35 p.D620N confers a gain-of-function with respect to LRRK2 kinase activity, and that VPS35 and LRRK2 functionally interact to regulate DAT function and striatal dopamine transmission.https://doi.org/10.1038/s41531-023-00609-7 |
| spellingShingle | Mengfei Bu Jordan Follett Isaac Deng Igor Tatarnikov Shannon Wall Dylan Guenther Melissa Maczis Genevieve Wimsatt Austen Milnerwood Mark S. Moehle Habibeh Khoshbouei Matthew J. Farrer Inhibition of LRRK2 kinase activity rescues deficits in striatal dopamine physiology in VPS35 p.D620N knock-in mice npj Parkinson's Disease |
| title | Inhibition of LRRK2 kinase activity rescues deficits in striatal dopamine physiology in VPS35 p.D620N knock-in mice |
| title_full | Inhibition of LRRK2 kinase activity rescues deficits in striatal dopamine physiology in VPS35 p.D620N knock-in mice |
| title_fullStr | Inhibition of LRRK2 kinase activity rescues deficits in striatal dopamine physiology in VPS35 p.D620N knock-in mice |
| title_full_unstemmed | Inhibition of LRRK2 kinase activity rescues deficits in striatal dopamine physiology in VPS35 p.D620N knock-in mice |
| title_short | Inhibition of LRRK2 kinase activity rescues deficits in striatal dopamine physiology in VPS35 p.D620N knock-in mice |
| title_sort | inhibition of lrrk2 kinase activity rescues deficits in striatal dopamine physiology in vps35 p d620n knock in mice |
| url | https://doi.org/10.1038/s41531-023-00609-7 |
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