Objective: We aim to investigate the potential roles of LRP10 defects in PD, PDD and DLB, focusing on two pathways known to be central in the pathogenesis of these disease: the secretory pathway and autophagy-lysosome pathway (ALP).
Background: Pathogenic loss-of-function variants in the LDL Receptor Related Protein 10 gene (LRP10) have been identified in families with late-onset Parkinson’s disease (PD), Parkinson’s disease dementia (PDD) and dementia with Lewy bodies (DLB). Several studies suggest that LRP10 function is linked to intracellular transport, however, how LRP10 variants lead to neurodegeneration remains unknown.
Method: Biochemical analyses, western blotting and immunocytochemistry were used to study ALP and secretory pathway function in wild type, LRP10 knock-out or LRP10 overexpressing HEK-293T cells, as well as in human iPSC derived astrocytes.
Results: Association of LRP10 with the secretory pathway was demonstrated by co-localization of endogenous LRP10 with markers of multivesicular bodies (MVBs) in iPSC derived astrocytes, and by the detection of overexpressed LRP10 in extracellular vesicles (EVs) isolated from conditioned media from HEK-293T cells. LRP10 connection with the ALP function was first revealed via drug-induced modulation of autophagic function, which was found to induce dramatic changes in endogenous LRP10 protein levels in iPSC derived astrocytes. Furthermore, immunocytochemistry experiments showed partial overlap of endogenous LRP10 and ALP markers, especially after blocking lysosomal acidification via the addition of bafilomycin A1. Interestingly, knock-out of LRP10 in HEK-293T cells lead to changes in expression levels of proteins associated with the ALP, including p62, Atg5 and LC3B-II.
Conclusion: In this study, we show that LRP10 is associated with the secretory pathway and ALP function, indicating that deregulation of these pathways might be important disease mechanisms in patients carrying LRP10 pathogenic variants.
To cite this abstract in AMA style:A. Carreras Mascaro, MM. Grochowska, V. Boumeester, V. Bonifati, W. Mandemakers. Parkinson’s disease-linked LDL Receptor Related Protein 10 (LRP10) is implicated in regulation of the secretory and autophagy-lysosome pathways [abstract]. Mov Disord. 2021; 36 (suppl 1). https://www.mdsabstracts.org/abstract/parkinsons-disease-linked-ldl-receptor-related-protein-10-lrp10-is-implicated-in-regulation-of-the-secretory-and-autophagy-lysosome-pathways/. Accessed December 7, 2023.
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MDS Abstracts - https://www.mdsabstracts.org/abstract/parkinsons-disease-linked-ldl-receptor-related-protein-10-lrp10-is-implicated-in-regulation-of-the-secretory-and-autophagy-lysosome-pathways/