c-Abl switches off parkin in Parkinson's brain

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

Han Seok Ko, Ted Dawson, Valina Dawson and colleagues at Johns Hopkins (PNAS, 2010; NIH extramural support per Europe PMC). Syed Z. Imam (University of Texas Health Science Center, San Antonio), Senlin Li, Robert Clark and colleagues (J Neurosci, 2011), a separate group. Funders were not read.

What happened

Parkin is a protein that tags other proteins for disposal; losing it causes juvenile Parkinson's (landmark 12). c-Abl is a "tyrosine kinase", an enzyme that adds phosphate tags to proteins. The Hopkins team showed c-Abl adds a tag at parkin's tyrosine 143, which blocks parkin's disposal-tagging activity.

• Dopamine-neuron stress (the toxins MPP+ and MPTP) activated c-Abl. Parkin then lost function, and two of its target proteins, AIMP2 and FBP1, piled up and cells died.
• STI-571 (imatinib, a leukaemia drug that blocks c-Abl) kept parkin active and protected cells. The protection needed parkin to be present. Removing c-Abl from the nervous system in mice protected them from MPTP.
• In postmortem brains of people with Parkinson's, c-Abl was active, parkin carried the phosphate tag, and AIMP2 and FBP1 had accumulated in the substantia nigra and striatum.
• The second group (Imam et al.) reached the same conclusion independently: oxidative and dopamine stress activated c-Abl, active c-Abl was found in the striatum of patients, and STI-571 restored parkin function in cells and mice.

Why it moved us toward a cure

It extends the parkin story from a rare inherited disease (landmark 12) to common sporadic Parkinson's: parkin may be disabled by a drug-blockable enzyme. That gave a reason to test c-Abl blockers, which became the nilotinib and later c-Abl trials (landmark 68). Suggested new parent link: 211 should be a parent of 68.

Outcome

Advanced. The mechanism led directly to human trials. Those trials have not shown benefit so far: nilotinib did not help and barely reached the brain (landmark 68); risvodetinib missed its main 12-week measure (landmark 174). Whether the tag-on-parkin mechanism drives human disease remains unproven; most evidence is from toxin models and postmortem tissue. The two 2010–11 papers reached the same conclusion from separate labs; later parkin–c-Abl work cited by reviews came from the Dawson lab (Karuppagounder 2014) and I found no further independent test of tyrosine 143. Europe PMC lists no correction or retraction for either paper.

Sources

• Ko et al., PNAS 2010;107:16691–16696, DOI 10.1073/pnas.1006083107, PMID 20823226 (abstract read via Europe PMC)
• Imam et al., J Neurosci 2011;31:157–163, DOI 10.1523/JNEUROSCI.1833-10.2011, PMID 21209200 (abstract read via Europe PMC)
• Not yet verified: full texts and patient numbers in the postmortem work; independent replication of the tyrosine 143 finding beyond the Imam paper; the first name of Li (shown as "Li S" in Europe PMC).