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Neurite Collapse and Altered ER Ca 2+ Control in Human Parkinson Disease Patient iPSC-Derived Neurons with LRRK2 G2019S Mutation.
Neurite Collapse and Altered ER Ca 2+ Control in Human Parkinson Disease Patient iPSC-Derived Neurons with LRRK2 G2019S Mutation.
- Source :
-
Stem cell reports [Stem Cell Reports] 2019 Jan 08; Vol. 12 (1), pp. 29-41. Date of Electronic Publication: 2018 Dec 27. - Publication Year :
- 2019
-
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 Ca <superscript>2+</superscript> influx sarco/ER Ca <superscript>2+</superscript> -ATPase inhibitor thapsigargin (THP). Baseline ER Ca <superscript>2+</superscript> levels measured with the ER Ca <superscript>2+</superscript> 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 Ca <superscript>2+</superscript> influx and decreased intracellular Ca <superscript>2+</superscript> 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 Ca <superscript>2+</superscript> entry regulators, with no alterations in ER Ca <superscript>2+</superscript> efflux. These results demonstrate PD gene mutation LRRK2 G2019S ER calcium-dependent pathogenic effects in human neurons.<br /> (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)
- Subjects :
- Cells, Cultured
Endoplasmic Reticulum metabolism
Humans
Mutation, Missense
Neurites drug effects
Neurites pathology
Parkinson Disease genetics
Thapsigargin pharmacology
Calcium Signaling
Induced Pluripotent Stem Cells metabolism
Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 genetics
Neurites metabolism
Parkinson Disease metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 2213-6711
- Volume :
- 12
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Stem cell reports
- Publication Type :
- Academic Journal
- Accession number :
- 30595548
- Full Text :
- https://doi.org/10.1016/j.stemcr.2018.11.021