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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 \u03b1-synuclein could be important for determining the mechanisms of non-motor symptoms. In PD models, expression of mutant LRRK2 reduces membrane localization of \u03b1-synuclein, and enhances formation of pathologic \u03b1-synuclein, particularly when synaptic activity is increased. \u03b1-Synuclein and LRRK2 both localize to the presynaptic terminal. LRRK2 plays a role in membrane traffic, including axonal transport, and therefore may influence \u03b1-synuclein synaptic localization. This study shows that LRRK2 kinase activity influences \u03b1-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 \u03b1-synuclein. Expansion microscopy (ExM) in primary hippocampal cultures and the mouse striatum, in vivo, was used to more precisely resolve the presynaptic localization of \u03b1-synuclein. Live imaging of axonal transport of \u03b1-synuclein-GFP was used to investigate the impact of LRRK2 kinase inhibition on \u03b1-synuclein axonal transport towards the presynaptic terminal. Reduced LRRK2 kinase activity increases \u03b1-synuclein overlap with presynaptic markers in primary neurons, and increases anterograde axonal transport of \u03b1-synuclein-GFP. In vivo, LRRK2 inhibition increases \u03b1-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 \u03b1-synuclein. These data provide potential mechanisms by which LRRK2-mediated perturbations of \u03b1-synuclein localization could cause pathology in both LRRK2-PD, and idiopathic PD.<\/jats:p>","DOI":"10.1186\/s40478-021-01283-7","type":"journal-article","created":{"date-parts":[[2021,11,8]],"date-time":"2021-11-08T11:02:43Z","timestamp":1636369363000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["Inhibition of LRRK2 kinase activity promotes anterograde axonal transport and presynaptic targeting of \u03b1-synuclein"],"prefix":"10.1186","volume":"9","author":[{"given":"Charlotte F.","family":"Brzozowski","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Baraa A.","family":"Hijaz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vijay","family":"Singh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nolwazi Z.","family":"Gcwensa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaela","family":"Kelly","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edward S.","family":"Boyden","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew B.","family":"West","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deblina","family":"Sarkar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8934-4018","authenticated-orcid":false,"given":"Laura A.","family":"Volpicelli-Daley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,11,8]]},"reference":[{"issue":"6645","key":"1283_CR1","doi-asserted-by":"publisher","first-page":"839","DOI":"10.1038\/42166","volume":"388","author":"MG Spillantini","year":"1997","unstructured":"Spillantini MG, Schmidt ML, Lee VM, Trojanowski JQ, Jakes R, Goedert M (1997) Alpha-synuclein in Lewy bodies. 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