A Rare Kidney Disease To Cure Them All? Towards Mechanism-Based Therapies for Proteinopathies

Moran Dvela-Levitt; Jillian L Shaw; Anna Greka

doi:10.1016/j.molmed.2020.11.008

A Rare Kidney Disease To Cure Them All? Towards Mechanism-Based Therapies for Proteinopathies

Trends Mol Med. 2021 Apr;27(4):394-409. doi: 10.1016/j.molmed.2020.11.008. Epub 2020 Dec 16.

Authors

Moran Dvela-Levitt¹, Jillian L Shaw², Anna Greka³

Affiliations

¹ The 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.
² The Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, USA.
³ The 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. Electronic address: agreka@bwh.harvard.edu.

PMID: 33341352
DOI: 10.1016/j.molmed.2020.11.008

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.

Keywords: MUC1 kidney disease; P24; TMED; autosomal dominant tubulointerstitial kidney disease (ADTKD); cargo quality control; chronic kidney disease; proteinopathies; rare diseases.

Publication types

Review

MeSH terms

Humans
Induced Pluripotent Stem Cells
Kidney / metabolism
Kidney Diseases / etiology
Kidney Diseases / genetics
Kidney Diseases / pathology
Mucin-1* / genetics
Mucin-1* / metabolism
Mutation
Organoids
Polycystic Kidney, Autosomal Dominant* / etiology
Polycystic Kidney, Autosomal Dominant* / genetics
Polycystic Kidney, Autosomal Dominant* / pathology
Proteostasis Deficiencies / genetics*

Substances

Mucin-1