One faulty copy of PINK1: risk not confirmed

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

Puschmann, Springer and colleagues (Brain, 2017). Krohn, Blauwendraat, Gan-Or and colleagues, with the International Parkinson's Disease Genomics Consortium (Neurobiology of Aging, 2020). Hu, Waters, Fon, Gan-Or and colleagues (Neurobiology of Aging, 2022).

What happened

Two broken copies of PINK1 cause young-onset Parkinson's (landmark 15). Many people carry one. Whether one broken copy raises risk matters for who carries risk and for mitophagy ("clearing damaged mitochondria") drugs. It is the same question as for PRKN (landmark 236).

• Puschmann 2017. In 2,560 patients and 2,145 controls, heterozygous (single-copy) G411S carriers had a higher risk (odds ratio 2.92, P = 0.032). Adding earlier studies (4,437 more people) gave 2.89 (P = 0.027). Cell work suggested the mutant protein partly blocks the normal one.
• Krohn 2020. Several data sets totalling 376,558 people (13,708 cases, 362,850 controls). The authors did not find evidence for heterozygous PINK1 mutations as a robust risk factor.
• Hu 2022. Burden tests of rare damaging single-copy variants in PRKN, PARK7 and PINK1: 5,829 cases and 7,221 controls with sequencing, plus counts from 9,501 cases and 48,207 controls. No significant excess in any of the three genes, in early- or late-onset disease. The authors want larger, more diverse cohorts.

Why it moved us toward a cure

Being a PINK1 carrier is not a clear warning sign, and mitophagy trials (landmark 15) should not assume single-copy carriers are at risk. Like PRKN (landmark 236), the early signals came from small studies. A small effect from specific variants such as G411S is not ruled out.

Outcome

Open, leaning to no general risk. The single-variant G411S signal has not been resolved by the large analyses I found.

Sources

• Puschmann et al., Brain 2017;140(1):98–117
• Krohn et al., Neurobiol Aging 2020;91:168.e1–5, DOI 10.1016/j.neurobiolaging.2020.03.003, PMID 32249012, PMC7236133 (abstract via Europe PMC)
• Hu et al., Neurobiol Aging 2022;119:136–138, DOI 10.1016/j.neurobiolaging.2022.07.012, PMID 36305379 (abstract via Europe PMC)
• Not yet verified: full texts of Krohn and Hu (only abstracts read); whether Krohn tested G411S specifically; the full Puschmann author list was not checked beyond the publisher page.