Parkin mutations cause juvenile parkinsonism

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

Tohru Kitada, Shuichi Asakawa, Nobutaka Hattori, Hiroto Matsumine, Yasuhiro Yamamura, Shinsei Minoshima, Masayuki Yokochi, Yoshikuni Mizuno and Nobuyoshi Shimizu. PubMed lists the Department of Neurology, Juntendo University School of Medicine, Tokyo, first; the other authors' institutions and the funders were not read.

What happened

The disease (autosomal recessive juvenile parkinsonism, AR-JP) had been mapped to chromosome 6q25.2–q27. By positional cloning within a deletion in one Japanese patient, the team isolated a gene of 12 exons spanning over 500 kilobases, encoding a 465-amino-acid protein with a ubiquitin-like start and a RING-finger end. Five exons (3–7) were deleted in that patient, and four other patients from three unrelated families lacked exon 4. The transcript is found in many tissues but is most abundant in brain, including the substantia nigra, and is shorter in brain tissue from one group of exon-4-deleted patients. The protein was named parkin. Nature 392:605–608, 1998.

Why it moved us toward a cure

It was the first recessive Parkinson's gene and showed that loss of a protein-disposal function can kill dopamine neurons. It later led to the parkin and mitophagy pathway (landmark 15).

Outcome

Advanced. Parkin loss of function is established as a cause of early-onset Parkinson's, and the pathway is now a drug-target area.

Sources

• Kitada et al., Nature 1998, DOI 10.1038/33416 (citation confirmed via Semantic Scholar)
• Alzforum note
• PubMed 9560156 (abstract read via Europe PMC; the patient and family counts above are from it)
• Not yet verified: the exact publication day (an earlier version said 9 April 1998); the later finding that parkin acts as an E3 ligase (Shimura 2000), which is not stated in the 1998 abstract.