LRP10 and alpha-synuclein secretion

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

Carreras Mascaro, Wim Mandemakers (corresponding author), Vincenzo Bonifati and eight colleagues at Erasmus MC, Rotterdam. The paper, titled "LRP10 and α-synuclein transmission in Lewy body diseases", is in Cellular and Molecular Life Sciences 2024;81:75. It was first posted as a preprint in May 2023. Funding listed: Alzheimer Nederland and Stichting ParkinsonFonds.

What happened

The 2018 gene report, landmark 193, left open whether rare LRP10 variants really cause Lewy body disease. This paper does not settle that. It asks a different question: what does LRP10 do?

In human brains, LRP10 is usually found in support cells (astrocytes) and blood vessels. In Parkinson's, Parkinson's dementia and dementia with Lewy bodies, it also shows up inside neurons in the Lewy bodies, the clumps rich in alpha-synuclein. The team used cultured cells, stem-cell-derived astrocytes and stem-cell-derived brain organoids and reported:

• Normal LRP10 is released in small packages called extracellular vesicles and can be taken up by other cells.
• LRP10 release is very sensitive to blocking autophagy (the cell's recycling).
• Overproducing LRP10 strongly increased secretion of single-molecule alpha-synuclein, and changed alpha-synuclein levels inside cells under stress.
• Astrocytes from a patient with the c.1424+5G>A variant released abnormal, larger forms of LRP10. This truncated form binds normal LRP10, lowers its level and blocks its effect on alpha-synuclein.

The authors call this "initial evidence" for a role of LRP10 in modulating alpha-synuclein.

Why it moved us toward a cure

It offers a possible mechanism for a disputed gene (landmark 193), tying it to alpha-synuclein handling and spread. If confirmed, it would add a second route into the synuclein pathway besides SNCA itself.

Outcome

Open. The work is in cell and organoid systems. It does not show LRP10 mutations cause disease, and genetic replication of the 2018 finding was mixed. Two 2026 mouse papers from one Taiwanese group (Wang et al.; funded by Taiwan's National Science and Technology Council) report movement deficits, loss of nigral dopamine neurons and phospho-synuclein deposits in Lrp10 knockout and G603R knock-in mice, and say normal LRP10 lowers synuclein mRNA. These are single-lab abstract-level reports, not yet replicated.

Sources

• Carreras Mascaro et al., Cell Mol Life Sci 2024;81:75, DOI 10.1007/s00018-024-05135-0 (abstract read via Europe PMC)
• Preprint, bioRxiv 2023, DOI 10.1101/2023.05.12.540510
• Wang et al., Neurochem Int 2026, DOI 10.1016/j.neuint.2026.106186 · Wang et al., Neurochem Res 2026, DOI 10.1007/s11064-026-04762-2
• Wang et al. 2026 appeared in Neurochemistry International; the second in Neurochemical Research. No correction or retraction is listed for the 2024 paper (PMID 38315424).
• Not yet verified: full text of any of these papers; any human genetic replication since 2021. Landmark 193 calls the 2024 paper a review; the abstract describes experiments, so that wording needs a correction (not my file).