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 with LRRK2-PD,...

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Autores principales:	Charlotte F. Brzozowski, Baraa A. Hijaz, Vijay Singh, Nolwazi Z. Gcwensa, Kaela Kelly, Edward S. Boyden, Andrew B. West, Deblina Sarkar, Laura A. Volpicelli-Daley
Formato:	article
Lenguaje:	EN
Publicado:	BMC 2021
Materias:	LRRK2 Parkinson’s disease α-synuclein Trafficking Presynaptic Synapse Neurology. Diseases of the nervous system RC346-429
Acceso en línea:	https://doaj.org/article/529d6d304c07412f8ead36c5d416d3e5
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spelling	oai:doaj.org-article:529d6d304c07412f8ead36c5d416d3e52021-11-14T12:11:12ZInhibition of LRRK2 kinase activity promotes anterograde axonal transport and presynaptic targeting of α-synuclein10.1186/s40478-021-01283-72051-5960https://doaj.org/article/529d6d304c07412f8ead36c5d416d3e52021-11-01T00:00:00Zhttps://doi.org/10.1186/s40478-021-01283-7https://doaj.org/toc/2051-5960Abstract 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.Charlotte F. BrzozowskiBaraa A. HijazVijay SinghNolwazi Z. GcwensaKaela KellyEdward S. BoydenAndrew B. WestDeblina SarkarLaura A. Volpicelli-DaleyBMCarticleLRRK2Parkinson’s diseaseα-synucleinTraffickingPresynapticSynapseNeurology. Diseases of the nervous systemRC346-429ENActa Neuropathologica Communications, Vol 9, Iss 1, Pp 1-18 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	LRRK2 Parkinson’s disease α-synuclein Trafficking Presynaptic Synapse Neurology. Diseases of the nervous system RC346-429
spellingShingle	LRRK2 Parkinson’s disease α-synuclein Trafficking Presynaptic Synapse Neurology. Diseases of the nervous system RC346-429 Charlotte F. Brzozowski Baraa A. Hijaz Vijay Singh Nolwazi Z. Gcwensa Kaela Kelly Edward S. Boyden Andrew B. West Deblina Sarkar Laura A. Volpicelli-Daley Inhibition of LRRK2 kinase activity promotes anterograde axonal transport and presynaptic targeting of α-synuclein
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.
format	article
author	Charlotte F. Brzozowski Baraa A. Hijaz Vijay Singh Nolwazi Z. Gcwensa Kaela Kelly Edward S. Boyden Andrew B. West Deblina Sarkar Laura A. Volpicelli-Daley
author_facet	Charlotte F. Brzozowski Baraa A. Hijaz Vijay Singh Nolwazi Z. Gcwensa Kaela Kelly Edward S. Boyden Andrew B. West Deblina Sarkar Laura A. Volpicelli-Daley
author_sort	Charlotte F. Brzozowski
title	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_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_sort	inhibition of lrrk2 kinase activity promotes anterograde axonal transport and presynaptic targeting of α-synuclein
publisher	BMC
publishDate	2021
url	https://doaj.org/article/529d6d304c07412f8ead36c5d416d3e5
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Inhibition of LRRK2 kinase activity promotes anterograde axonal transport and presynaptic targeting of α-synuclein

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