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Inhibition of LRRK2 kinase activity promotes anterograde axonal transport and presynaptic targeting of α-synuclein

Charlotte F. Brzozowski, Baraa A. Hijaz, Vijay Singh, Nolwazi Z. Gcwensa, Kaela Kelly, View ORCID ProfileEdward S. Boyden, View ORCID ProfileAndrew B. West, Deblina Sarkar, View ORCID ProfileLaura A. Volpicelli-Daley
doi: https://doi.org/10.1101/2021.10.04.463043
Charlotte F. Brzozowski
1Department of Neurology, Center for Neurodegeneration and Experimental therapeutics, University of Alabama at Birmingham, Birmingham, AL 35294 USA
2Interfaculty Institute for Biochemistry, University of Tübingen, 72076 Tübingen, Germany
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Baraa A. Hijaz
1Department of Neurology, Center for Neurodegeneration and Experimental therapeutics, University of Alabama at Birmingham, Birmingham, AL 35294 USA
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Vijay Singh
1Department of Neurology, Center for Neurodegeneration and Experimental therapeutics, University of Alabama at Birmingham, Birmingham, AL 35294 USA
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Nolwazi Z. Gcwensa
1Department of Neurology, Center for Neurodegeneration and Experimental therapeutics, University of Alabama at Birmingham, Birmingham, AL 35294 USA
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Kaela Kelly
3Duke Center for Neurodegeneration Research, Department of Pharmacology and Cancer Biology, Duke University, Durham, North Carolina, USA
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Edward S. Boyden
4McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, MA 02139 USA; Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139 USA; Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02139 USA
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Andrew B. West
3Duke Center for Neurodegeneration Research, Department of Pharmacology and Cancer Biology, Duke University, Durham, North Carolina, USA
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Deblina Sarkar
5MIT Media Lab, Departments of Biological Engineering and Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139 USA
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Laura A. Volpicelli-Daley
1Department of Neurology, Center for Neurodegeneration and Experimental therapeutics, University of Alabama at Birmingham, Birmingham, AL 35294 USA
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  • For correspondence: lvolpicellidaley@uabmc.edu
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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.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • Author emails: Charlotte Brzozowski cfbrzozo{at}uab.edu; Baraa Hijaz bhijaz{at}hms.harvard.edu; Vijay Singh vijaysingh{at}uabmc.edu; Nolwazi Z. Gcwensa gcwenolw{at}uab.edu; Kaela Kelly kaela.kelly{at}arvinas.com; Edward S. Boyden esb{at}media.mit.edu; Andrew B. West andrew.west{at}duke.edu; Deblina Sarkar deblina{at}mit.edu.

  • List of Abbreviations

    DAT
    Dopamine transporter
    ExM
    Expansion microscopy
    LRRK2
    Leucine-rich repeat kinase 2
    MCC
    Mander’s Colocalization coefficient
    PD
    Parkinson’s disease
    VAMP2
    vesicle-associated membrane protein 2
    vGLUT1
    vesicular glutamate transporter 1
  • Copyright 
    The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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    Inhibition of LRRK2 kinase activity promotes anterograde axonal transport and presynaptic targeting of α-synuclein
    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
    bioRxiv 2021.10.04.463043; doi: https://doi.org/10.1101/2021.10.04.463043
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    Inhibition of LRRK2 kinase activity promotes anterograde axonal transport and presynaptic targeting of α-synuclein
    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
    bioRxiv 2021.10.04.463043; doi: https://doi.org/10.1101/2021.10.04.463043

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