Inhibition of LRRK2 kinase activity promotes anterograde axonal transport and presynaptic targeting of α-synuclein
Abstract Pathologic inclusions composed of α-synuclein called Lewy pathology are hallmarks of Parkinson’s Disease (PD). Dominant inherited mutations in leucine rich repeat kinase 2 (LRRK2) are the most common genetic cause of PD. Lewy pathology is found in the majority of individuals...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BioMed Central
2021
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| Online Access: | https://hdl.handle.net/1721.1/138128 |
| _version_ | 1826190034426920960 |
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| author | Brzozowski, Charlotte F. Hijaz, Baraa A. Singh, Vijay Gcwensa, Nolwazi Z. Kelly, Kaela Boyden, Edward S. West, Andrew B. Sarkar, Deblina Volpicelli-Daley, Laura A. |
| author2 | McGovern Institute for Brain Research at MIT |
| author_facet | McGovern Institute for Brain Research at MIT Brzozowski, Charlotte F. Hijaz, Baraa A. Singh, Vijay Gcwensa, Nolwazi Z. Kelly, Kaela Boyden, Edward S. West, Andrew B. Sarkar, Deblina Volpicelli-Daley, Laura A. |
| author_sort | Brzozowski, Charlotte F. |
| collection | MIT |
| description | Abstract
Pathologic inclusions composed of α-synuclein called Lewy pathology are hallmarks of Parkinson’s Disease (PD). Dominant inherited mutations in leucine rich repeat kinase 2 (LRRK2) are the most common genetic cause of PD. Lewy pathology is found in the majority of individuals with LRRK2-PD, particularly those with the G2019S-LRRK2 mutation. Lewy pathology in LRRK2-PD associates with increased non-motor symptoms such as cognitive deficits, anxiety, and orthostatic hypotension. Thus, understanding the relationship between LRRK2 and α-synuclein could be important for determining the mechanisms of non-motor symptoms. In PD models, expression of mutant LRRK2 reduces membrane localization of α-synuclein, and enhances formation of pathologic α-synuclein, particularly when synaptic activity is increased. α-Synuclein and LRRK2 both localize to the presynaptic terminal. LRRK2 plays a role in membrane traffic, including axonal transport, and therefore may influence α-synuclein synaptic localization. This study shows that LRRK2 kinase activity influences α-synuclein targeting to the presynaptic terminal. We used the selective LRRK2 kinase inhibitors, MLi-2 and PF-06685360 (PF-360) to determine the impact of reduced LRRK2 kinase activity on presynaptic localization of α-synuclein. Expansion microscopy (ExM) in primary hippocampal cultures and the mouse striatum, in vivo, was used to more precisely resolve the presynaptic localization of α-synuclein. Live imaging of axonal transport of α-synuclein-GFP was used to investigate the impact of LRRK2 kinase inhibition on α-synuclein axonal transport towards the presynaptic terminal. Reduced LRRK2 kinase activity increases α-synuclein overlap with presynaptic markers in primary neurons, and increases anterograde axonal transport of α-synuclein-GFP. In vivo, LRRK2 inhibition increases α-synuclein overlap with glutamatergic, cortico-striatal terminals, and dopaminergic nigral-striatal presynaptic terminals. The findings suggest that LRRK2 kinase activity plays a role in axonal transport, and presynaptic targeting of α-synuclein. These data provide potential mechanisms by which LRRK2-mediated perturbations of α-synuclein localization could cause pathology in both LRRK2-PD, and idiopathic PD. |
| first_indexed | 2024-09-23T08:34:00Z |
| format | Article |
| id | mit-1721.1/138128 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T08:34:00Z |
| publishDate | 2021 |
| publisher | BioMed Central |
| record_format | dspace |
| spelling | mit-1721.1/1381282023-04-19T19:18:10Z Inhibition of LRRK2 kinase activity promotes anterograde axonal transport and presynaptic targeting of α-synuclein Brzozowski, Charlotte F. Hijaz, Baraa A. Singh, Vijay Gcwensa, Nolwazi Z. Kelly, Kaela Boyden, Edward S. West, Andrew B. Sarkar, Deblina Volpicelli-Daley, Laura A. McGovern Institute for Brain Research at MIT Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences Howard Hughes Medical Institute Massachusetts Institute of Technology. Media Laboratory Abstract Pathologic inclusions composed of α-synuclein called Lewy pathology are hallmarks of Parkinson’s Disease (PD). Dominant inherited mutations in leucine rich repeat kinase 2 (LRRK2) are the most common genetic cause of PD. Lewy pathology is found in the majority of individuals with LRRK2-PD, particularly those with the G2019S-LRRK2 mutation. Lewy pathology in LRRK2-PD associates with increased non-motor symptoms such as cognitive deficits, anxiety, and orthostatic hypotension. Thus, understanding the relationship between LRRK2 and α-synuclein could be important for determining the mechanisms of non-motor symptoms. In PD models, expression of mutant LRRK2 reduces membrane localization of α-synuclein, and enhances formation of pathologic α-synuclein, particularly when synaptic activity is increased. α-Synuclein and LRRK2 both localize to the presynaptic terminal. LRRK2 plays a role in membrane traffic, including axonal transport, and therefore may influence α-synuclein synaptic localization. This study shows that LRRK2 kinase activity influences α-synuclein targeting to the presynaptic terminal. We used the selective LRRK2 kinase inhibitors, MLi-2 and PF-06685360 (PF-360) to determine the impact of reduced LRRK2 kinase activity on presynaptic localization of α-synuclein. Expansion microscopy (ExM) in primary hippocampal cultures and the mouse striatum, in vivo, was used to more precisely resolve the presynaptic localization of α-synuclein. Live imaging of axonal transport of α-synuclein-GFP was used to investigate the impact of LRRK2 kinase inhibition on α-synuclein axonal transport towards the presynaptic terminal. Reduced LRRK2 kinase activity increases α-synuclein overlap with presynaptic markers in primary neurons, and increases anterograde axonal transport of α-synuclein-GFP. In vivo, LRRK2 inhibition increases α-synuclein overlap with glutamatergic, cortico-striatal terminals, and dopaminergic nigral-striatal presynaptic terminals. The findings suggest that LRRK2 kinase activity plays a role in axonal transport, and presynaptic targeting of α-synuclein. These data provide potential mechanisms by which LRRK2-mediated perturbations of α-synuclein localization could cause pathology in both LRRK2-PD, and idiopathic PD. 2021-11-15T12:58:27Z 2021-11-15T12:58:27Z 2021-11-08 2021-11-14T04:13:15Z Article http://purl.org/eprint/type/JournalArticle https://hdl.handle.net/1721.1/138128 Acta Neuropathologica Communications. 2021 Nov 08;9(1):180 PUBLISHER_CC en https://doi.org/10.1186/s40478-021-01283-7 Creative Commons Attribution https://creativecommons.org/licenses/by/4.0/ The Author(s) application/pdf BioMed Central BioMed Central |
| spellingShingle | Brzozowski, Charlotte F. Hijaz, Baraa A. Singh, Vijay Gcwensa, Nolwazi Z. Kelly, Kaela Boyden, Edward S. West, Andrew B. Sarkar, Deblina Volpicelli-Daley, Laura A. Inhibition of LRRK2 kinase activity promotes anterograde axonal transport and presynaptic targeting of α-synuclein |
| title | Inhibition of LRRK2 kinase activity promotes anterograde axonal transport and presynaptic targeting of α-synuclein |
| title_full | Inhibition of LRRK2 kinase activity promotes anterograde axonal transport and presynaptic targeting of α-synuclein |
| title_fullStr | Inhibition of LRRK2 kinase activity promotes anterograde axonal transport and presynaptic targeting of α-synuclein |
| title_full_unstemmed | Inhibition of LRRK2 kinase activity promotes anterograde axonal transport and presynaptic targeting of α-synuclein |
| title_short | Inhibition of LRRK2 kinase activity promotes anterograde axonal transport and presynaptic targeting of α-synuclein |
| title_sort | inhibition of lrrk2 kinase activity promotes anterograde axonal transport and presynaptic targeting of α synuclein |
| url | https://hdl.handle.net/1721.1/138128 |
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