Format

Send to

Choose Destination
Nat Med. 2020 Feb;26(2):289-299. doi: 10.1038/s41591-019-0739-1. Epub 2020 Jan 27.

iPSC modeling of young-onset Parkinson's disease reveals a molecular signature of disease and novel therapeutic candidates.

Author information

1
Cedars-Sinai Board of Governors Regenerative Medicine Institute, Los Angeles, CA, USA.
2
Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
3
Center for Bioinformatics and Functional Genomics, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
4
Department of Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, CA, USA.
5
Samuel Oschin Comprehensive Cancer Institute, Los Angeles, CA, USA.
6
Research Division of Immunology, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
7
Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
8
Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
9
Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
10
Cedars-Sinai Board of Governors Regenerative Medicine Institute, Los Angeles, CA, USA. clive.svendsen@cshs.org.

Abstract

Young-onset Parkinson's disease (YOPD), defined by onset at <50 years, accounts for approximately 10% of all Parkinson's disease cases and, while some cases are associated with known genetic mutations, most are not. Here induced pluripotent stem cells were generated from control individuals and from patients with YOPD with no known mutations. Following differentiation into cultures containing dopamine neurons, induced pluripotent stem cells from patients with YOPD showed increased accumulation of soluble α-synuclein protein and phosphorylated protein kinase Cα, as well as reduced abundance of lysosomal membrane proteins such as LAMP1. Testing activators of lysosomal function showed that specific phorbol esters, such as PEP005, reduced α-synuclein and phosphorylated protein kinase Cα levels while increasing LAMP1 abundance. Interestingly, the reduction in α-synuclein occurred through proteasomal degradation. PEP005 delivery to mouse striatum also decreased α-synuclein production in vivo. Induced pluripotent stem cell-derived dopaminergic cultures reveal a signature in patients with YOPD who have no known Parkinson's disease-related mutations, suggesting that there might be other genetic contributions to this disorder. This signature was normalized by specific phorbol esters, making them promising therapeutic candidates.

PMID:
31988461
DOI:
10.1038/s41591-019-0739-1

Supplemental Content

Full text links

Icon for Nature Publishing Group
Loading ...
Support Center