Lrp10-flox Mouse

Lrp10, the low-density lipoprotein receptor-related protein 10, encodes a conserved cell surface protein. It has an impact on CD8 T-cell fate by suppressing IL7R levels post-translationally, thus influencing CD8 T-cell homeostatic expansion and anti-tumor immunity [1]. In the context of the nervous system, it may be involved in intracellular vesicle trafficking pathways through interaction with SORL1 in non-neuronal brain cells [2].

Forward genetic screening in mice showed that loss-of-function mutations in Lrp10 lead to the accumulation of naive and central memory CD8 T cells in peripheral lymphoid organs. Lrp10-deficient mice are resistant to syngeneic tumors due to dense CD8 T-cell infiltration with enhanced memory cell characteristics and reduced terminal exhaustion [1]. In neurodegenerative diseases, Lrp10 variants have been associated with Parkinson's disease (PD), PD dementia, dementia with Lewy bodies (DLB), progressive supranuclear palsy, and amyotrophic lateral sclerosis. In non-neuronal brain cells of control subjects, Lrp10 is highly expressed, while in neurons, it is undetectable. In some PD and DLB patients with Lrp10 variants, enlarged LRP10-positive vesicles were detected, and LRP10 was found in Lewy bodies at late maturation stages [2]. Also, in LBDs, wild-type LRP10 is secreted via extracellular vesicles and can be internalized. LRP10 overexpression affects α-synuclein levels, and a patient-derived LRP10 variant binds to wild-type LRP10, reducing its levels and affecting α-synuclein distribution [3].

In summary, Lrp10 is a key regulator in CD8 T-cell homeostasis and anti-tumor immunity, likely through its suppression of IL7R. In neurodegenerative diseases, especially those related to Lewy bodies, Lrp10 may play a role in disease pathogenesis through its involvement in vesicle trafficking and interaction with proteins like α-synuclein. Mouse models, especially those with Lrp10 loss-of-function mutations, have been crucial in uncovering these functions and their implications in disease [1,2,3].