PARIS builds up when parkin fails

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

Joo-Ho Shin, Han Seok Ko, Ted Dawson, Valina Dawson and colleagues, Johns Hopkins (Cell 144:689–702, 2011; NINDS funding listed).

What happened

Parkin tags proteins for disposal (landmark 12). The team found PARIS, a zinc-finger protein that parkin tags for destruction.

• PARIS accumulated in models where parkin was inactivated, and in human Parkinson's brain.
• PARIS binds the promoter of PGC-1α and switches it down, along with PGC-1α's target NRF-1. PGC-1α drives mitochondrial production and defences against oxidative stress.
• Removing parkin in adult mice caused progressive loss of dopamine neurons, and this depended on PARIS. Overproducing PARIS alone killed nigral dopamine neurons, and extra parkin or extra PGC-1α reversed it.

Why it moved us toward a cure

It gives a concrete chain from a recessive gene (landmark 12) to energy failure and cell loss, and it names a handle (lower PARIS, or raise PGC-1α) that drug projects could target.

Outcome

Open. No PARIS-targeting drug has reached patients as far as I verified. The result is from mouse and cell models plus postmortem tissue. Follow-ups: the same group's 2025 conditional-transgenic mouse paper (Kim et al., Mol Neurodegener) again found PARIS in dopamine neurons caused progressive neuron loss, and tested c-Abl inhibitors; an independent Polish study (Dorszewska et al., IBRO Neurosci Rep 2025; 100 patients, 125 controls) found plasma Parkin lower and ZNF746 higher in patients, supporting the link but in a small, indirect measure. No correction or retraction was found for the 2011 paper.

Sources

• Shin et al., Cell 2011;144:689–702, DOI 10.1016/j.cell.2011.02.010, PMID 21376232 (abstract read via Europe PMC)
• Kim et al., Mol Neurodegener 2025, DOI 10.1186/s13024-025-00814-3 · Dorszewska et al., IBRO Neurosci Rep 2025, DOI 10.1016/j.ibneur.2025.01.016
• Not yet verified: replication of the mouse neuron-loss result by a group independent of the Dawson and Shin labs; any PARIS-directed therapy; funders beyond NINDS; PubPeer not checked.