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

Jenna L Tancredi¹  Michael C DeSantis¹  Erin K O'Shea¹  Andrew L Lemire¹  Aurelie de Rus Jacquet¹  Wei-Ping Li¹ 

[1] Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, United States;

关键词: neurodegenerative diseases;    neuron-glia interactions;    non-cell autonomous;    neurodegeneration;    Parkinson's disease;    exosomes;    Human;    Mouse;   

DOI  :  10.7554/eLife.73062

来源: eLife Sciences Publications, Ltd

【 摘 要 】

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.

【 授权许可】

CC BY