VPS13C recessive 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

Suzanne Lesage, Alexis Brice and colleagues (220 listed authors, Paris Brain Institute and an international consortium; Am J Hum Genet 2016;98:500–513). Funded by the French National Research Agency, the France-Parkinson Association, the Roger de Spoelberch Foundation, the French Academy of Sciences, the European Joint Programme on Neurodegenerative Disease, and the US National Institute on Aging and National Institute of Neurological Disorders and Stroke intramural programmes.

What happened

Using homozygosity mapping and exome sequencing in 62 people with early-onset parkinsonism and consanguinity, and then exomes from 1,348 people with Parkinson's, the team found truncating VPS13C variants in three unrelated people. The disease was early, fast and severe, with early cognitive decline. Neuropathology resembled diffuse Lewy body disease.

In cell models, VPS13C sat partly on the outer mitochondrial membrane. Silencing it lowered mitochondrial membrane voltage, fragmented the mitochondria, raised respiration and increased PINK1/parkin-dependent mitophagy, with higher PARK2 (parkin) transcription after mitochondrial damage.

Why it moved us toward a cure

It is a third gene feeding the mitochondrial quality-control story begun with parkin (landmark 12) and PINK1 (landmark 15), and it adds a lipid-transfer angle. Later work showed VPS13C is a lipid transfer protein at contacts between the endoplasmic reticulum and lysosomes, and that losing it activates the cGAS-STING innate immune pathway (Hancock-Cerutti et al., J Cell Biol 2022) and impairs lysosome repair (Adeosun et al., Nat Commun 2026), so its main role may be in the lysosome rather than the mitochondrion.

Outcome

Open. Rare. No therapy targets VPS13C. No correction or retraction was found for the 2016 paper; a Mov Disord comment accompanied it.

Sources

• Lesage et al., Am J Hum Genet 2016;98(3):500–513, DOI 10.1016/j.ajhg.2016.01.014, PMID 26942284 (abstract and funding via Europe PMC and PMC4800038; HAL copy)
• Hancock-Cerutti et al., J Cell Biol 2022, DOI 10.1083/jcb.202106046 · Adeosun et al., Nat Commun 2026, DOI 10.1038/s41467-026-75145-y (abstracts via Europe PMC)
• Not yet verified: whether common VPS13C variants appear in Parkinson's GWAS; the number of further families reported since 2016.