CHARACTERIZATION OF LRP10 EXPRESSION IN LEWY BODY DISORDERS AND IPSC-DERIVED BRAIN CELLS

OBJECTIVE: Our objective is to characterize endogenous low-density lipoprotein-related protein 10 (LRP10) expression in human induced pluripotent stem cell (iPSC)-derived brain cell types, post-mortem brain tissue from idiopathic Parkinson’s disease (PD) and Dementia with Lewy Bodies (DLB) cases, and a unique series of PD or DLB patients carrying rare LRP10 variants.
BACKGROUND: Loss-of-function variants in LRP10 have been identified in patients with familial PD, PD-dementia, and DLB. In spite of this genetic evidence, little is known about LRP10 function and expression in the central nervous system under physiological and pathological conditions.
METHODS: Characterization and validation of two novel LRP10 antibodies. Generation of human iPSC-derived neural progenitors, midbrain dopaminergic neurons (mDANs) and astrocytes. Biochemical analyses and detailed multi-label laser scanning confocal microscopy to study LRP10 (sub-)cellular distribution in iPSC-derived cells and in adult human brains from control subjects and patients diagnosed with PD and DLB. Co-immunoprecipitation of LRP10 with the sortilin related receptor 1 (SORL1) protein.
RESULTS: Using two knockout validated LRP10 antibodies, we show that iPSC-derived astrocytes have higher LRP10 protein expression when compared to neural progenitors or mDANs. Similarly, we demonstrate that in adult human brain LRP10 is mainly expressed in astrocytes and neurovascular unit, but is undetectable in neurons. In astrocytes, endogenous LRP10 is localised to vesicular structures, including trans-Golgi network, endosomes, and retromer. Interestingly, LRP10 also partially co-localises and interacts with SORL1. Finally, we demonstrate that LRP10-positive vesicles are present in the core of mature Lewy bodies of idiopathic PD and DLB, as well as in PD or DLB patients carrying rare LRP10 variants.
CONCLUSION: High expression of LRP10 in astrocytes and undetectable expression levels in dopaminergic neurons point towards potential involvement of LRP10 in PD and DLB through cell non-autonomous mechanisms, potentially via disturbance of interaction with SORL1 in vesicle trafficking pathways. Together with the finding of LRP10-positive vesicles in the core of nigral LBs, these data suggest an important role for deregulated vesicle trafficking in PD and DLB. Future research should explore the roles of astrocytes and the molecular mechanisms influenced by the loss of LRP10 function in neurodegeneration.