PINK1 and parkin share a pathway (flies)

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

Three groups in 2006: Clark and colleagues (Ming Guo's lab; Nature 441:1162–1166, May), Park and colleagues (Jongkyeong Chung's lab; Nature 441:1157–1161) and Yang and colleagues (Bingwei Lu's lab; PNAS 103:10793–10798, July).

What happened

Parkin (landmark 12) and PINK1 (landmark 15) were separate genes for juvenile parkinsonism. In flies, loss of Pink1 caused mitochondrial damage and muscle degeneration (all three papers), and in Park and Yang also loss of dopamine neurons. Clark found fly parkin mutants look like Pink1 mutants and that extra parkin rescued the Pink1 defects. Park found that transgenic Parkin ameliorated all PINK1 loss-of-function phenotypes "but not vice versa", which puts Parkin downstream of PINK1. Yang found Parkin, but not DJ-1, suppressed the Pink1 phenotypes and that Parkin protein was reduced in Pink1-knockdown flies.

Why it moved us toward a cure

It joined two genes into one pathway on failing mitochondria. In 2010 two groups showed in mammalian cells that PINK1 builds up on damaged mitochondria and recruits Parkin to start mitophagy (Narendra et al., PLoS Biol; Matsuda et al., J Cell Biol), the logic behind mitophagy-boosting drugs.

Outcome

Advanced. The pathway was later worked out in mammalian cells (see above). Park's and Yang's dopamine-neuron loss was in flies only, and whether the fly findings predict drug effects in people is untested here.

Sources

• Clark et al., Nature 2006, DOI 10.1038/nature04779 · Park et al., Nature 2006, DOI 10.1038/nature04788 · Yang et al., PNAS 2006, DOI 10.1073/pnas.0602493103 (abstracts confirmed in Europe PMC) · Narendra et al., PLoS Biol 2010;8:e1000298, DOI 10.1371/journal.pbio.1000298, PMID 20126261 · Matsuda et al., J Cell Biol 2010;189:211–221, DOI 10.1083/jcb.200910140, PMID 20404107
• Not yet verified: Clark's dopamine-neuron findings and the exact end of its abstract (cut off in the record read); full texts; the link from this pathway to USP30 inhibitors (removed, no source read).