LRP10

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

Mario Quadri, Wim Mandemakers, Vincenzo Bonifati and colleagues (Erasmus MC, Rotterdam), with the International Parkinsonism Genetics Network, Lancet Neurology 2018. Europe PMC lists funding from Stichting Lijf en Leven, the European Commission, Parkinson's UK, ZonMw, the EU Joint Programme on Neurodegenerative Disease Research and Erasmus MC.

What happened

• Family. Linkage analysis in an Italian family of ten affected people (mean onset 59.8 years) pointed to chromosome 14 and the gene LRP10.
• Screen. Among 660 unrelated probands, 8 carried different rare variants (4 with Parkinson's, 2 with Parkinson's dementia, 2 with dementia with Lewy bodies), versus 1 in 645 controls (people with abdominal aortic aneurysms who were not examined neurologically). Three more Parkinson's patients with two of the variants turned up in Sardinia and Taiwan, none in controls.
• Segregation. Nine of ten affected relatives carried the variant. Brain autopsy in three carriers showed severe Lewy body pathology (landmark 5). Cell tests suggested loss of LRP10 function.

Replication was mixed:

• Vergouw 2019 (130 patients, South-West Netherlands) found three rare variants in four patients and none in 62 controls, one shared by two genealogically linked patients, supporting the claim.
• Li 2021 (385 Han Chinese familial probands) found four variants; only one clearly co-segregated, one did not, and there was no excess of rare variants versus controls. The authors called for more evidence.
• Challenge in print. In December 2018 Lancet Neurology ran five letters titled "LRP10 in α-synucleinopathies", from Kia et al., Guerreiro et al. (International DLB Genetics Consortium; a repository copy is titled "Lack of evidence for LRP10 variants as a cause of dementia with Lewy bodies"), Pihlstrøm et al. (MSA exome consortium), Tesson et al. and Shi et al., with the authors' reply. Only the Guerreiro title was read; the letters' data were not.

Why it moved us toward a cure

It is a candidate for a synucleinopathy gene alongside the confirmed SNCA mutations (landmark 44). A Dutch group later reported that LRP10 may regulate how synuclein is handled by cells (Carreras Mascaro 2024, an experimental cell study; see landmark 232), though it does not settle LRP10's role. If real, loss of LRP10 would point to a mechanism where less is worse, which matters for drug design.

Outcome

Open and disputed. The strongest evidence is Dutch and Italian; other cohorts show rare variants in patients and controls alike. LRP10 is not among the seven core genes (LRRK2, GBA, PRKN, PINK1, SNCA, PARK7, VPS35) that the ClinGen Parkinson's gene panel set out to curate first (from a search summary of a conference abstract), and no ClinGen or MDSGene verdict was found. A 2025 preprint reports that LRP10 helps move progranulin and prosaposin to lysosomes (Filippini et al., bioRxiv).

Sources

• Quadri et al., Lancet Neurol 2018;17(7):597–608, DOI 10.1016/S1474-4422(18)30179-0, PMID 29887161 (abstract via Europe PMC). Linked items on PubMed: a Lancet Neurol comment by Ross and Bu (17:571–573, DOI 10.1016/S1474-4422(18)30214-X), five letters (17:1032–1035, DOIs 10.1016/S1474-4422(18)30399-5, -30400-9, -30401-0, -30402-2, -30407-1), a Mov Disord 2019 commentary by Morgante and Valente (34:47), the authors' reply (DOI 10.1016/S1474-4422(18)30408-3) and a correction, Lancet Neurol 2020;19:e2 whose content could not be read
• Vergouw et al., Parkinsonism Relat Disord 2019, DOI 10.1016/j.parkreldis.2019.05.037 · Li et al., Neurobiol Aging 2021, DOI 10.1016/j.neurobiolaging.2020.08.015
• Quadri et al., authors' reply, Lancet Neurol 2018, DOI 10.1016/S1474-4422(18)30408-3 · Carreras Mascaro et al., Cell Mol Life Sci 2024, DOI 10.1007/s00018-024-05135-0
• Filippini et al., bioRxiv 2025, DOI 10.1101/2025.05.02.651888 (preprint; title only)
• Not yet verified: the content of the five letters, the 2018 comment and the 2020 correction; whether the correction changed any number above; the preprint's findings (no lysosome tag is used); current ClinGen or MDSGene status. A PanelApp Australia page rating LRP10 for early-onset Parkinson's was found only through a search summary and could not be read.