Understanding the role of LIMP-2 in the lysosomal storage disorder Fabry Disease

Cross-Talk of Cells in the Heart 2025 (University of Birmingham, UK) (2025) Proc Physiol Soc 66, C15

Poster Communications: Understanding the role of LIMP-2 in the lysosomal storage disorder Fabry Disease

Megan Douglas1, Alex Davies1, Susan Kimber1, Karen Piper-Hanley1, Matthew Birket1

1University of Manchester United Kingdom

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Fabry disease (FD) is a progressive, X-linked lysosomal storage disorder characterised by globotriaosylceramide (Gb3) accumulation and widespread cellular dysfunction. Although FD affects multiple organ systems, cardiac complications remain the leading cause of patient mortality and current diagnostic methods and therapies remain inadequate. A major barrier to diagnosis and treatment is that the mechanisms of the disease remain poorly understood. Focusing on heart involvement, our lab generated an induced pluripotent stem cell (iPSC) model of FD and identified the lysosomal membrane protein LIMP-2 as a protein which accumulates in FD iPSC-derived cardiomyocytes. Since its functional role in the heart remains unexplored, this study aimed to address this and understand better the disease cascade downstream of Gb3 accumulation. LIMP-2 expression was altered via CRISPR-Cas9 knockout and lentiviral overexpression. LIMP-2 knockout iPSCs were obtained, they remained pluripotent and could be differentiated to cardiomyocytes with high efficiency. Samples were submitted for Gb3 quantification by mass spectrometry and whole cell proteomics (n = 5). Early candidate testing identified the gap junction protein Cx43, as significantly increased (n = 3, P < 0.05) after LIMP-2 overexpression, suggesting Cx43 could be a potential target of LIMP-2. Cx43 has recently been implicated in mediating lysosomal exocytosis under cell stress, hence its upregulation in response to elevated LIMP-2 levels could suggest a cardioprotective mechanism employed to aid Gb3 clearance in FD. Understanding these mechanisms could support the development of better diagnostic methods and therapies for patients with FD and other lysosomal storage disorders.



Where applicable, experiments conform with Society ethical requirements.

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