Neurite Collapse and Altered ER Ca²⁺ Control in Human Parkinson Disease Patient iPSC-Derived Neurons with LRRK2 G2019S Mutation.

ABSTRACT: The Parkinson disease (PD) genetic LRRK2 gain-of-function mutations may relate to the ER pathological changes seen in PD patients at postmortem. Human induced pluripotent stem cell (iPSC)-derived neurons with the PD pathogenic LRRK2 G2019S mutation exhibited neurite collapse when challenged with the ER Ca²⁺ influx sarco/ER Ca²⁺-ATPase inhibitor thapsigargin (THP). Baseline ER Ca²⁺ levels measured with the ER Ca²⁺ indicator CEPIA-ER were lower in LRRK2 G2019S human neurons, including in differentiated midbrain dopamine neurons in vitro. After THP challenge, PD patient-derived neurons displayed increased Ca²⁺ influx and decreased intracellular Ca²⁺ buffering upon membrane depolarization. These effects were reversed following L

SUBMITTER: Korecka JA 

PROVIDER: S-EPMC6335600 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature