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A Rare Kidney Disease To Cure Them All? Towards Mechanism-Based Therapies for Proteinopathies
Moran Dvela-Levitt1, Jillian L Shaw2, Anna Greka1
1The Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, USA; Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
Abstract:
Autosomal dominant tubulointerstitial kidney diseases (ADTKDs) are a group of rare genetic diseases that lead to kidney failure. Mutations in the MUC1 gene cause ADTKD-MUC1 (MUC1 kidney disease, MKD), a disorder with no available therapies. Recent studies have identified the molecular and cellular mechanisms that drive MKD disease pathogenesis. Armed with patient-derived cell lines and pluripotent stem cell (iPSC)-derived kidney organoids, it was found that MKD is a toxic proteinopathy caused by the intracellular accumulation of misfolded MUC1 protein in the early secretory pathway. We discuss the advantages of studying rare monogenic kidney diseases, describe effective patient-derived model systems, and highlight recent mechanistic insights into protein quality control that have implications for additional proteinopathies beyond rare kidney diseases.
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