Dataset Information

An iPSC Model of Early Onset Parkinson's Disease

ABSTRACT: Early onset Parkinson’s Disease (onset <50 years) accounts for between 10-20 percent of all patients. While some of these cases are associated with specific mutations, the majority are sporadic where the cause is unknown. We generated induced pluripotent stem cells from sporadic early onset patients and differentiated them to dopamine neurons. At early stages in culture (30 days) we found significant elevations in soluble α-synuclein protein levels when compared to controls. This was associated with reductions in lysosomal membrane proteins such as LAMP1 and an increase in phosphorylated protein kinase C-α (p-PKCα). Testing activators of lysosomal function showed that specific phorbal esters reduced both α-synuclein and p-PKCα levels and increased LAMP1 expression. Interestingly, very low doses of the drug PEP005 were able to reduce α-synuclein levels without affecting p-PKCα. Similar effects of PEP005 on α-synuclein expression were seen following infusion into the mouse brain. Our data show that early onset sporadic Parkinson’s Disease can be accurately predicted using a ratio of α-synuclein and p-PKCα in dopamine neural cultures derived from patient iPSC’s and that specific phorbal esters can alter both biomarkers making these drugs promising candidates to treat Parkinson’s Disease.

INSTRUMENT(S): TripleTOF 6600

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Dopaminergic Neuron, Stem Cell, Cell Culture

DISEASE(S): Parkinson's Disease

SUBMITTER: Victoria Dardov

LAB HEAD: Jennifer Van Eyk

PROVIDER: PXD011326 | Pride | 2019-12-06

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	2017Aug31_PD_idopaneurons.interact.comet.pep.xml	Pepxml
	2017Aug31_PD_idopaneurons.interact.kscore.pep.xml	Pepxml
	2017Aug31_PD_idopaneurons.interact.native.pep.xml	Pepxml
	2017Aug31_PD_idopaneurons_SpecLib_iRT_cons_openswath_decoys.TraML	Other
	2017Aug31_PD_idopaneurons_SpecLib_iRT_cons_openswath_decoys_featurealignment_output.tsv	Tabular

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Publications

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

Laperle A H AH Sances S S Yucer N N Dardov V J VJ Garcia V J VJ Ho R R Fulton A N AN Jones M R MR Roxas K M KM Avalos P P West D D Banuelos M G MG Shu Z Z Murali R R Maidment N T NT Van Eyk J E JE Tagliati M M Svendsen C N CN

Nature medicine 20200127 2

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 o ...[more]

PMID: 31988461

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