iSCORE-PD: an isogenic stem cell collection to research Parkinson Disease

By Oriol Busquets Figueras, PhD, Hanqin Li, PhD, Khaja Mohieddin Syed, PhD, Pilar Alvarez Jerez, Jesse Dunnack, BSc, Riana Lo Bu, Yogendra Verma, MSc, Gabriella Rita Pangilinan, Annika Martin, Jannes Straub, MSc, Victoria (YuXin) Du, BA, Vivien M. Simon, Steven Poser, PhD, Zipporiah Bush, BSc, Jessica Diaz, BSc, Atehsa Sahagun, BSc, Jianpu Gao, Dena Hernandez, Kristin S Levine, Ezgi Booth, PhD, Helen Bateup, PhD, Donald Rio, PhD, Dirk Hockemeyer, PhD, Cornelis Blauwendraat, PhD and Frank Soldner, MD

View Published Article View Preprint

Description

Parkinson's disease (PD) is a neurodegenerative disorder caused by complex genetic and environmental factors. Genome-edited human pluripotent stem cells (hPSCs) offer the uniique potential to advance our understanding of PD etiology by providing disease-relevant cell-types carrying patient mutations along with isogenic control cells. To facilitate this experimental approach, we generated a collection of 55 cell lines genetically engineered to harbor mutations in genes associated with monogenic PD (SNCA A53T, SNCA A30P, PRKN Ex3del, PINK1 Q129X, DJ1/PARK7 Ex1-5del, LRRK2 G2019S, ATP13A2 FS, FBXO7 R498X/FS, DNAJC6 c.801 A>G+FS, SYNJ1 R258Q/FS, VPS13C A444P, VPS13C W395C, GBA1 IVS2+1). All mutations were generated in a fully characterized and sequenced female human embryonic stem cell (hESC) line (WIBR3; NIH approval number NIHhESC-10-0079) using CRISPR/Cas9 or prime editing-based approaches. We implemented rigorous quality controls, including high density genotyping to detect structural variants and confirm the genomic integrity of each cell line. This systematic approach ensures the high quality of our stem cell collection, highlights differences between conventional CRISPR/Cas9 and prime editing and provides a roadmap for how to generate gene-edited hPSCs collections at scale in an academic setting. We expect that our isogenic stem cell collection will become an accessible platform for the study of PD, which can be used by investigators to understand the molecular pathophysiology of PD in a human cellular setting.

Identifier (DOI)

10.1101/2024.02.12.579917

Tags

ATP13A2
CRISPR
DJ-1
DNAJC6
Female
GBA1
Human embryonic stem cells (hESC)
Isogenic
LRRK2
Parkinson's disease
PE (Prime editing)
PINK1
SNCA
SYNJ1
VPS13C
WIBR3

Program

Global Parkinson's Genetics Program

Theme

PD Functional Genomics

Meet the Authors

Oriol Busquets Figueras, PhD

Key Personnel: Team Rio,

Albert Einstein College of Medicine
Hanqin Li, PhD

Key Personnel: Team Rio,

University of California, Berkeley
Khaja Mohieddin Syed, PhD

Key Personnel: Team Rio,

University of California, Berkeley
Pilar Alvarez Jerez
Jesse Dunnack, BSc

Key Personnel: Team Rio,

University of California, Berkeley
Riana Lo Bu

Key Personnel: Team Rio,

Albert Einstein College of Medicine
Yogendra Verma, MSc

Key Personnel: Team Rio,

University of California, Berkeley
Gabriella Rita Pangilinan

Key Personnel: Team Rio,

University of California, Berkeley
Annika Martin
Jannes Straub, MSc

Key Personnel: Team Rio, Team Voet,

VIB-KU Leuven Center for Brain & Disease Research
Victoria (YuXin) Du, BA

Key Personnel: Team Rio,

University of California, Berkeley
Vivien M. Simon
Steven Poser, PhD

Key Personnel: Team Rio,

University of Washington
Zipporiah Bush, BSc

Key Personnel: Team Rio,

Albert Einstein College of Medicine
Jessica Diaz, BSc

Key Personnel: Team Rio,

Albert Einstein College of Medicine
Atehsa Sahagun, BSc

Key Personnel: Team Rio,

University of California, Berkeley
Jianpu Gao
Dena Hernandez
Kristin S Levine
Ezgi Booth, PhD

Project Manager: Team Rio,

University of California, Berkeley
Helen Bateup, PhD

Co-PI (Core Leadership): Team Rio,

University of California, Berkeley
Donald Rio, PhD

Lead PI (Core Leadership): Team Rio,

University of California, Berkeley
Dirk Hockemeyer, PhD

Co-PI (Core Leadership): Team Rio,

University of California, Berkeley
Cornelis Blauwendraat, PhD

Coalition for Aligning Science
Frank Soldner, MD

Co-PI (Core Leadership): Team Rio,

Albert Einstein College of Medicine