UCHL1 I93M (PARK5)

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

Elke Leroy, Rebecca Boyer, Mihael Polymeropoulos and colleagues, Nature 1998 ("The ubiquitin pathway in Parkinson's disease").

What happened

Ubiquitin is a tag that marks proteins for disposal. UCHL1 (ubiquitin C-terminal hydrolase L1) is an enzyme in that system and is very abundant in neurons. The team reported an isoleucine-to-methionine change at position 93 (I93M) in a single German family with Parkinson's; the locus was named PARK5. The abstract says the change causes a partial loss of the enzyme's activity. A later paper describes the family as a sibling pair.

Later work did not support it as a cause in the wider population:

• A German screen of sporadic and familial patients found no disease-causing change in the UCHL1 coding region (Wintermeyer et al., NeuroReport 2000;11:2079).
• A 2021 sequencing study of UCHL1 and four other disputed genes (2,408 patients, 3,444 controls) found no association and said the "PARK" label for these genes should be reconsidered (Saini et al., Neurobiol Aging 2021).
• A separate common variant, S18Y, has been studied as a protective or risk factor. Results conflict: Wintermeyer and a Japanese study (Miyake 2012, BMC Neurol) reported a lower risk, while others found none (Mellick 2000; Hutter 2008; a 2014 Asian meta-analysis, Sun et al., Neurol Sci).

Why it moved us toward a cure

It was an early push to link the cell's disposal machinery to Parkinson's, in the same year as the parkin gene (landmark 12), which is an enzyme of the same system, and a year after the first gene (landmark 4). The parkin finding held up and became a major branch. UCHL1 did not, so it is a warning that one family is not enough to call a gene.

Outcome

Dead end (the gene claim did not hold up). Parkin, PINK1 and the lysosome genes carried the "disposal" idea forward; a 2021 sequencing study found no association for UCHL1. It is a dead-end claim rather than a refuted one, because the original family has not been formally disproved.

Sources

• Leroy et al., Nature 1998;395:451–452, DOI 10.1038/26652, PMID 9774100
• Miyake et al., UCHL1 S18Y in Japan, BMC Neurol 2012, DOI 10.1186/1471-2377-12-62 · Hutter et al., Eur J Neurol 2008, DOI 10.1111/j.1468-1331.2007.02012.x · Sun et al., Neurol Sci 2014, DOI 10.1007/s10072-014-1973-4
• Wintermeyer et al., NeuroReport 2000, PMID 10923647 · Mellick and Silburn, Neurosci Lett 2000, PMID 11027850 (S18Y, Australian sample of 142 cases and 142 controls; also describes I93M as found in a sib-pair) · Saini et al., Neurobiol Aging 2021, PMID 33239198
• Not yet verified: the family details of the 1998 paper (pedigree size, enzyme activity figures); the Japanese I93M screen (74 sporadic patients, 155 controls), dropped from the text because no source was found; whether any later family has carried I93M.