Dopamine oxidation damages the lysosome

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

Lena Burbulla, Dimitri Krainc and colleagues at Northwestern University (16 authors), including Joseph Mazzulli, Rejko Krüger and D. James Surmeier (Science, 22 Sep 2017). Funding named in the paper included US National Institutes of Health grants, the JPB Foundation, the Michael J. Fox Foundation and the IDP Foundation (to Surmeier), and a German Academic Exchange Service fellowship (to Burbulla).

What happened

The team grew dopamine neurons from stem cells of people with inherited and sporadic Parkinson's. They described a time-dependent cascade: mitochondrial oxidant stress led to oxidised dopamine; this reduced activity of glucocerebrosidase (GCase, the enzyme encoded by GBA; landmark 16); the lysosome (the cell's recycling bin) became dysfunctional and alpha-synuclein accumulated. The cascade appeared in the human neurons but not mouse neurons, partly because the two species handle dopamine differently. Raising dopamine production or synuclein levels in mouse midbrain neurons reproduced the changes. Science 357:1255-1261.

Why it moved us toward a cure

It offered a possible reason why the same genes damage dopamine neurons first: these cells make a reactive chemical (dopamine) that turns toxic when mitochondria falter. It joined three previously separate threads, mitochondria (landmark 11, 15), the lysosome (landmark 35) and synuclein, into one chain, and it implies several possible places to intervene, including restoring GCase activity (landmark 40).

Outcome

Open. The chain is shown in cultured human neurons and not demonstrated in living patients. The human-versus-mouse difference also complicates animal testing of any drug aimed at it. No therapy based directly on this finding was identified in the sources read. No correction or retraction was found; two commentaries (Mov Disord, Trends Neurosci) accompanied the paper.

Sources

• Burbulla et al., Science 2017;357(6357):1255-1261, DOI 10.1126/science.aam9080, PMID 28882997 (abstract via Europe PMC; funding from PMC6021018) · abstract via Luxembourg repository
• Not yet verified: the number of patient lines; any follow-up showing the cascade in patient tissue; any drug developed from it.