The LRRK2 G2019S mutation alters astrocyte-to-neuron communication via extracellular vesicles and induces neuron atrophy in a human iPSC-derived model of Parkinson's disease

  1. Aurelie de Rus Jacquet  Is a corresponding author
  2. Jenna L Tancredi
  3. Andrew L Lemire
  4. Michael C DeSantis
  5. Wei-Ping Li
  6. Erin K O'Shea
  1. Janelia Research Campus, Howard Hughes Medical Institute, United States

Abstract

Astrocytes are essential cells of the central nervous system, characterized by dynamic relationships with neurons that range from functional metabolic interactions and regulation of neuronal firing activities, to the release of neurotrophic and neuroprotective factors. In Parkinson's disease (PD), dopaminergic neurons are progressively lost during the course of the disease, but the effects of PD on astrocytes and astrocyte-to-neuron communication remains largely unknown. This study focuses on the effects of the PD-related mutation LRRK2 G2019S in astrocytes generated from patient-derived induced pluripotent stem cells. We report the alteration of extracellular vesicle (EV) biogenesis in astrocytes, and we identify the abnormal accumulation of key PD-related proteins within multi vesicular bodies (MVBs). We found that dopaminergic neurons internalize astrocyte-secreted EVs and that LRRK2 G2019S EVs are abnormally enriched in neurites and fail to provide full neurotrophic support to dopaminergic neurons. Thus, dysfunctional astrocyte-to-neuron communication via altered EV biological properties may participate in the progression of PD.

Data availability

Sequencing data have been deposited in GEO under accession codes GSE152768.

The following data sets were generated

Article and author information

Author details

  1. Aurelie de Rus Jacquet

    Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, United States
    For correspondence
    aurelie.jacquet@crchudequebec.ulaval.ca
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5548-8045
  2. Jenna L Tancredi

    Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, United States
    Competing interests
    No competing interests declared.
  3. Andrew L Lemire

    Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0624-3789
  4. Michael C DeSantis

    Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7214-2740
  5. Wei-Ping Li

    Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, United States
    Competing interests
    No competing interests declared.
  6. Erin K O'Shea

    Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, United States
    Competing interests
    Erin K O'Shea, is Chief Scientific Officer and a Vice President at the Howard Hughes Medical Institute, one of the three founding funders of eLife..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2649-1018

Funding

No external funding was received for this work

Reviewing Editor

  1. Hugo J Bellen, Baylor College of Medicine, United States

Ethics

Animal experimentation: Primary cultures were prepared via dissection of P1 to P3 mouse pups obtained from C57BL/6NTac WT mice or constitutive LRRK2 G2019S knock-in mice generated and maintained on the C57BL/6NTac background (Matikainen-Ankney et al., 2016) (Taconic Biosciences, NY) using methods approved by the Janelia Institutional Animal Care and Use Committee (IACUC protocol #18-168).

Human subjects: Patient-derived induced pluripotent stem cells were obtained from RUCDR Infinite Biologics, a University-based biorepository. A second line was provided by Prof. Dr. Thomas Gasser (Universitätsklinikum Tübingen) and Prof. Dr. Hans R. Schöler (Max-Planck Institute), for which informed consent was obtained from all patients prior to cell donation and the Ethics Committee of the Medical Faculty and the University Hospital Tübingen previously approved this consent form (see publication by Reinhardt et al., 2013. Cell Stem Cell, doi 10.1016/j.stem.2013.01.008).

Version history

  1. Preprint posted: July 2, 2020 (view preprint)
  2. Received: August 15, 2021
  3. Accepted: September 28, 2021
  4. Accepted Manuscript published: September 30, 2021 (version 1)
  5. Version of Record published: October 13, 2021 (version 2)

Copyright

© 2021, de Rus Jacquet et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Aurelie de Rus Jacquet
  2. Jenna L Tancredi
  3. Andrew L Lemire
  4. Michael C DeSantis
  5. Wei-Ping Li
  6. Erin K O'Shea
(2021)
The LRRK2 G2019S mutation alters astrocyte-to-neuron communication via extracellular vesicles and induces neuron atrophy in a human iPSC-derived model of Parkinson's disease
eLife 10:e73062.
https://doi.org/10.7554/eLife.73062

Share this article

https://doi.org/10.7554/eLife.73062

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