POLG mutations cause 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

Pauliina Luoma (Helsinki University and Helsinki University Central Hospital), Atle Melberg, Juha Rinne, Anders Oldfors, Anu Suomalainen and colleagues. Lancet 364:875–882, 4 September 2004.

What happened

POLG makes the enzyme that copies mitochondrial DNA (mtDNA), the small DNA ring inside each mitochondrion. Mutations in POLG were known to cause progressive external ophthalmoplegia (PEO, a slow loss of eye-muscle control) with multiple mtDNA deletions.

The team studied seven families of varied ethnic origin with PEO. Every family carried POLG mutations. Parkinsonism ran with the mutations (P < 0.0001), and the paper's title links the disease to premature menopause as well. PET scans were consistent with loss of dopamine neurons. Autopsies of two people showed loss of pigmented neurons in the substantia nigra, but no Lewy bodies. The affected tissue also held extra mtDNA deletions. Most women had premature menopause, before age 35.

Why it moved us toward a cure

Earlier evidence that mitochondria fail in Parkinson's was correlational, such as complex I deficiency (landmark 11). Here a primary defect in mtDNA maintenance was linked to parkinsonism in families, so mitochondrial damage can be a cause, not only a result. It sits beside PINK1 and parkin in the same year (landmark 15). Two papers in 2006 then showed mtDNA deletions in nigral neurons (landmark 81).

Outcome

Open. POLG parkinsonism is rare and, in the two autopsies, had no Lewy bodies, so how well it models ordinary Parkinson's is unclear. Later clinical reports exist (Synofzik et al. 2010 on dopaminergic response in POLG-associated parkinsonism) and a 2012 screen found POLG mutations infrequent in atypical parkinsonism, but no therapy has come from it.

Sources

• Luoma et al., Lancet 2004;364:875–882, DOI 10.1016/S0140-6736(04)16983-3, PubMed 15351195
• Synofzik et al., Mov Disord 2010;25:243–245, DOI 10.1002/mds.22865, PMID 19998270 · Synofzik et al., J Neurol 2012;259:2232–2233, DOI 10.1007/s00415-012-6535-1 (titles and citations only)
• Not yet verified: the number of people with parkinsonism (not in the abstract); whether POLG is a risk gene in ordinary Parkinson's (the 2010 and 2012 papers' contents were not read); whether PINK1, reported in the same year, makes "first" wrong (the abstract's own wording is that none had been characterised).