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

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.

Astrocytes in Neurodegeneration: Inspiration From Genetics

“…Astrocyte atrophy was found in the derived astrocytes from PD patients with LRRK2 G2019S mutation (Table 1; Ramos-Gonzalez et al, 2021). LRRK2 G2019S mutated astrocyte from hiPSC appeared to cause nutritional damage to the DAergic neurons, damage the ATP supply, lowmitochondrial density, and ER disorder (de Rus Jacquet et al, 2021). Moreover, autophagy dysfunction was observed in astrocytes derived from LRRK2 G2019S mutated iPSCs (di Domenico et al, 2019; Figure 1).…”

Proteomic Alterations and Novel Markers of Neurotoxic Reactive Astrocytes in Human Induced Pluripotent Stem Cell Models

“…Over the past years, multiple studies from independent laboratories have demonstrated that hiPSC modeling is a powerful tool for uncovering the role of astrocytes in CNS diseases, including AD ( Oksanen et al, 2017 ; Preman et al, 2021 ; de Leeuw et al, 2022 ), Parkinson’s disease ( di Domenico et al, 2019 ; de Rus Jacquet et al, 2021 ; Ramos-Gonzalez et al, 2021 ; Russ et al, 2021 ; Trudler et al, 2021 ) and amyotrophic lateral sclerosis ( Birger et al, 2019 ; Zhao et al, 2020 ; Szebényi et al, 2021 ; Ziff et al, 2021 ; Giacomelli et al, 2022 ). Developing human models is particularly critical since such diseases cannot be fully recapitulated in animal systems and thus require multiple integrated approaches (i.e., combination of human and animal studies) to understand their pathogenic mechanisms.…”

The Future of Genetic Disease Studies: Assembling an Updated Multidisciplinary Toolbox

“…Further, the CRISPR revolution has provided the means to reproduce and study pathological protein variants within meaningful and physiologically relevant contexts ( Freedman et al, 2015 ; Ponomareva et al, 2016 ) as well as perform targeted rescue of disease-causing mutations in model systems ( Min et al, 2020 ). These developments become synergistic with the possibility of reprogramming patient-derived induced Pluripotent Stem Cells (iPSCs) to study cell biological behavior of mutated variants expressed at endogenous levels in disease-relevant cell types and organoids ( Parfitt et al, 2016 ; Boutry et al, 2018 ; Dvela-Levitt et al, 2019 ; Flemming et al, 2020 ; De Rus Jacquet et al, 2021 ; Romano et al, 2021 ).…”