A familial missense variant in the AD gene impairs its maturation and endosomal sorting

AUTHORS

Fazeli E , Child DD , Bucks SA , Stovarsky M , Edwards G , Yu CE , Latimer C , Kitago Y , Bird T , Andersen OM , Jayadev S , Young JE , . bioRxiv : the preprint server for biology. 2023 7 5; ().

PMID: 37461597 [PubMed].

ABSTRACT

The gene has recently emerged as a strong Alzheimer Disease risk gene. Over 500 different variants have been identified in the gene and the contribution of individual variants to AD development and progression is still unknown. Here, we describe a multi-generational family with both early- and late-onset AD in two generations. Exome sequencing identified a coding variant, p.(Arg953Cys), in in 4 of 5 individuals affected by AD. Notably, variant carriers had severe AD pathology, including the presence of Aβ plaques in the cerebellum as well as TDP-43 pathology. We further characterized this variant and show that this Arginine substitution occurs at a critical domain position of the translation product, SORL1. studies further show that the p.R953C variant has decreased maturation and shedding of the SORL1 protein, and also leads to mis-localization within cells. Together, our analysis suggests that p.R953C is a likely pathogenic variant of and sheds light on mechanisms of how missense SORL1 variants may lead to AD.

Tags: 2023 Alumni Publications