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 remain 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 identify the abnormal accumulation of key PD-related proteins within multivesicular 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.
Highlights
The loss of dopaminergic neurons in the substantia nigra pars compacta is associated with the severe and debilitating motor dysfunction observed in Parkinson’s disease (PD) patients (Massano & Bhatia, 2012)
We obtained induced pluripotent stem cells 93 (iPSCs) reprogrammed from the dermal fibroblasts of two patients with the LRRK2 G2019S mutation, and one line was gene-corrected to produce an isogenic control (Reinhardt et al., 2013) while the second line was paired with iPSCs derived from a sex- and age-matched healthy individual (Figure 1-figure supplement 1A-C)
We previously showed that WT and LRRK2 G2019S multi vesicular bodies (MVBs) contain similar levels of the CD63 tetraspanin (Figure 3-figure supplement 1A,B), and an ELISA-based quantification confirmed that the number of CD63+ extracellular vesicle (EV) remained unchanged between the two genotypes (Figure 3- figure supplement 1F)
Summary
The loss of dopaminergic neurons in the substantia nigra pars compacta is associated with the severe and debilitating motor dysfunction observed in Parkinson’s disease (PD) patients (Massano & Bhatia, 2012). The cause of dopaminergic neuron degeneration has been under intense investigation and has revealed the roles played by cellular stressors such as oxidative stress, mitochondrial dysfunction and disruption of protein degradation pathways (Dawson & Dawson, 2003; Lynch-Day, Mao, Wang, Zhao, & Klionsky, 2012) The dysregulation of these pathways within the neurons themselves reflect cell-autonomous mechanisms of neurodegeneration, but neurons exist in a highly dynamic multicellular environment in which non-neuronal cells may contribute to neuron loss (Allen & Lyons, 2018; Liddelow & Barres, 2017). Astrocytes with the LRRK2 G2019S mutation were found to alter neuronal morphology in a non-cell-autonomous fashion and shuttle detrimental astrocyte-derived alpha synuclein (αSyn) to co-cultured neurons (di Domenico et al, 2019) These observations suggest that disease astrocytes undergo important functional changes that affect the viability of neurons. Further studies of the effects of PD-related mutations on the functionality of astrocytes and their ability to support neuronal survival are greatly needed, as much remains to be discovered to fully appreciate the unique contributions of astrocytes to PD pathogenesis
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