LRP10 Gene Variants Implicated in Parkinson Disease, Lewy Body Dementia

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Investigators found that LRP10 protein localizes to vesicular structures at endosomes, the trans-Golgi network, and plasma membrane of human induced pluripotent stem cell-derived neurons.
Investigators found that LRP10 protein localizes to vesicular structures at endosomes, the trans-Golgi network, and plasma membrane of human induced pluripotent stem cell-derived neurons.

Mutations in the LRP10 gene appear to be common in patients with inherited α-synucleinopathies, including Parkinson disease (PD), PD dementia, and dementia with Lewy bodies, according to a study results published in Lancet Neurology. In addition, LRP10 variants correlate with severe Lewy pathology burden in the brain.

A genome-wide linkage analysis of an Italian family (n=10) featuring dominantly inherited PD was performed to identify the PD locus. Investigators also sequenced an international multicenter series comprised of 660 unrelated probands diagnosed with either PD, PD dementia, or dementia with Lewy bodies. Gene sequencing data from patients with abdominal aortic aneurysms were used as controls. In addition, an independent series of individuals with PD and individuals with no signs or familial history of PD or dementia were enrolled and screened for genetic variants.

Significant linkage of PD to chromosome 14 and LRP10 as the disease-causing gene was found in the Italian family. In the unrelated probands, a total of 8 patients carried rare and potentially pathogenic LRP10 variants. In addition, 10 probands with LRP10 variants had a family history of neurodegenerative disease, with LRP10 variants present in 9 of the 10 affected relatives. Definite LRP10 was associated with severe Lewy body pathology in a post-mortem analysis of 3 patients.

The 3 variants that had a severe impact on LRP10 expression and mRNA stability were 1424+5delG, 1424+5G→A, and Ala212Serfs*17.  In addition, 4 variants affected protein stability, including Tyr307Asn, Gly603Arg, Arg235Cys, and Pro699Ser, whereas Asn517del and Arg533Leu variants affected protein localization. These findings suggested loss of LRP10 function to be a primary driver for pathogenesis.

A limitation of the analysis included the disproportionately greater number of controls enrolled from Taiwan compared with other countries.

The researchers suggested that future understanding “of the normal function of LRP10 protein and its signaling pathways might offer crucial insights into the molecular mechanisms of inherited, and perhaps sporadic, α-synucleinopathies, pointing to novel biomarkers and therapeutic targets.”

Reference

Quadri M1, Mandemakers W1, Grochowska MM, et al; for the International Parkinsonism Genetics Network. LRP10 genetic variants in familial Parkinson's disease and dementia with Lewy bodies: a genome-wide linkage and sequencing study. Lancet Neurol. 2018;17(7):597-608.

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