
AsianScientist (Aug. 30, 2017) – In an international study, researchers from Japan, Spain and the US have identified a protein degradation defect that causes the symptoms associated with a rare kidney and liver disease. Their findings, published in Scientific Reports, could lead to new treatments from the poorly understood disease.
Autosomal recessive polycystic disease (ARPKD) is a rare disease affecting 1 in 20,000 people. Many infants born with this disease fail to see their first birthday, and those who survive often suffer from a litany of ailments including hypertension, cyst formation and tissue scarring. Treatments normally target the symptoms of the disease because the underlying molecular causes are poorly understood.
At the genetic level, ARPKD is known to be caused by a mutation in the PKHD1 gene. To identify key candidate molecules that contribute to the disease, Associate Professor Jun-Ya Kaimori from Osaka University and his colleagues compared cells from PKHD1 mutant and normal mice. They discovered that PKHD1 deficiency in cells resulted in abnormalities in cell shape.
“PKDH1 encodes the fibrocystin/polyductin complex (FPC). In cells with reduced levels of PKHD1, RhoA expression was elevated,” said Kaimori.
Because the RhoA protein is intimately involved in the control of cell morphology, the researchers focused their efforts on a group of proteins known as ubiquitin ligases that regulate RhoA levels in cells. In normal cells, three members of the E3 ubiquitin ligase family of proteins were found to colocalize with the FPC, whereas in mutant cells, the three ligases were abnormally distributed.
Without the proper localization of the ubiquitin ligases at the FPC, RhoA was not degraded, accumulating within cells and causing changes in morphology. These changes in cell morphology were eventually found to be associated with cyst genesis, liver and kidney fibrosis, and hypertension in PKDH1 mutant mice.
The researchers hope that by identifying other ubiquitin ligases that interact with FPC and RhoA, a better understanding of ARPKD will emerge and promising targets for future medicines can be identified.
The article can be found at: Kaimori et al. (2017) NEDD4-family E3 Ligase Dysfunction Due to PKHD1/Pkhd1 Defects Suggests a Mechanistic Model for ARPKD Pathobiology.
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Source: Osaka University; Photo: Shutterstock.
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