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

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 LRRK2 mutation correction by antisense oligonucleotides and gene editing. Gene expression analysis in LRRK2 G2019S neurons identified modified levels of key store-operated Ca2+ entry regulators, with no alterations in ER Ca2+ efflux. These results demonstrate PD gene mutation LRRK2 G2019S ER calcium-dependent pathogenic effects in human neurons. [Display omitted] •Parkinson-linked LRRK2 G2019S induces neurite collapse upon ER Ca2+ influx block•LRRK2 G2019S mutation alters Ca2+ uptake and buffering upon ER Ca2+ influx block•The LRRK2 G2019S mutation decreases basal ER Ca2+ levels in human iPSC neurons•The LRRK2 G2019S mutation modifies gene expression of key SOCE regulators Korecka, Isacson, and colleagues show that human iPSC-derived neurons with the Parkinson disease (PD) LRRK2 G2019S mutation have decreased basal ER calcium levels. Upon ER calcium influx inhibition, the LRRK2 G2019S PD patient neurons show specific and reversible neurite collapse and altered calcium uptake and buffering. These results demonstrate LRRK2 G2019S ER calcium-dependent pathogenic effects in human neurons.