Patient-derived dopamine neurons

The research record

This is the project's file for this landmark, as written and checked. Sources are listed at the end; anything not yet confirmed is marked "Not yet verified".

Who

Ha Nam Nguyen, Renee Reijo Pera, Theo Palmer and colleagues (LRRK2); Blake Byers, Palmer, Reijo Pera, William Langston and colleagues (SNCA triplication); and Michael Devine, Tilo Kunath, Patrick Lewis, John Hardy and colleagues (SNCA triplication, separate patient). Daniel Schöndorf, Michela Deleidi and Thomas Gasser led the GBA1 work (2014). Funders listed in Europe PMC: NIH (NHLBI, NINDS) for the LRRK2 paper, Howard Hughes Medical Institute for Byers, Parkinson's UK, MRC, Wellcome Trust and BBSRC for Devine, Telethon for Schöndorf.

What happened

Building on cell reprogramming (landmark 32), three 2011 papers made induced stem cells from patients and turned them into midbrain dopamine neurons. The LRRK2 G2019S neurons (Nguyen, Cell Stem Cell 8:267–280) showed higher levels of oxidative-stress genes and of synuclein, and more caspase-3 activation (a cell-death signal) when exposed to hydrogen peroxide, the proteasome blocker MG-132 or 6-OHDA. Byers (PLoS ONE 6:e26159) found neurons from a patient with an SNCA triplication (landmark 14) accumulated synuclein and were more sensitive to peroxide. Devine (Nat Commun 2:440) compared a triplication patient with an unaffected first-degree relative; the patient's neurons made about twice as much synuclein. In 2014, GBA1 patient neurons showed lower GCase activity, higher glucosylceramide and synuclein, and autophagy and calcium defects that were reversed by correcting the mutation (Nat Commun 5:4028; landmark 16).

Why it moved us toward a cure

For the first time human neurons carrying the actual patient genetics could be studied and used to screen drugs, for instance compounds that lower synuclein, as Devine's team proposed. In the GBA work, correcting the mutation reversed the defects, showing they came from the gene.

Outcome

Advanced as a platform: the same approach produced the GBA1 lines in 2014. Each 2011 study used one patient (or one patient and one relative), so findings needed replication. No correction or retraction was found for any of the four papers.

Sources

• Nguyen et al., Cell Stem Cell 2011;8:267–280, DOI 10.1016/j.stem.2011.01.013 (CIRM record, PubMed 21362567)
• Byers et al., PLoS ONE 2011;6(11):e26159, DOI 10.1371/journal.pone.0026159 (CIRM record, PubMed 22110584) · Alzforum citation page
• Devine et al., Nat Commun 2011;2:440, DOI 10.1038/ncomms1453
• Hargus et al., PNAS 2010 (earlier Parkinson's patient iPSC dopamine neurons), DOI 10.1073/pnas.1010209107
• Schöndorf et al., Nat Commun 2014;5:4028, DOI 10.1038/ncomms5028
• Not yet verified: the Nguyen paper's lead-lab institutions; later drug screens on these lines. Earlier patient-derived Parkinson's lines existed (Hargus 2010 made dopamine neurons from patient iPSCs), so these were not the first Parkinson's patient lines; PubPeer not checked.