EDITOR'S CHOICE IN CELL & MOLECULAR BIOLOGY
S.A. Zlatic et al., “Rare disease mechanisms identified by genealogical proteomics of copper homeostasis mutant pedigrees,” Cell Systems, 6:368-80.e6, 2018.
PARSING THE PROTEOME
Discovering the molecular mechanisms underlying disease-causing genetic mutations can be challenging. Biologists Stephanie Zlatic and Victor Faundez of Emory University took a novel approach to this problem: they compared the proteomes of patients with Menkes disease, a rare disorder, to those of healthy relatives. People with the condition have a single-gene mutation that prevents their bodies from regulating levels of copper, which is needed for normal growth and development and is integral to some metabolic pathways. The metal’s depletion results in developmental delays, intellectual disabilities, and, often, death.
FINDING NEW PATHWAYS
This genealogical proteomics approach allows researchers to identify disease pathways that are otherwise hard to tease apart, even if the specific gene causing the disorder is not known, says Zlatic. The research team looked for protein expression traits linked to Menkes, and found 214 proteins whose expression was altered in people with the disease.
A SURPRISING FIND
Proteins that were more abundant in the proteomes of people with Menkes included some that are involved in the UCHL1/PARK5 pathway, which plays a role in ubiquitin signaling and has been linked to Parkinson’s. “We didn’t intend to find anything related to Parkinson’s—this was the surprise of the study,” says Faundez. The researchers discovered previously unreported mechanisms by which the UCHL1/PARK5 pathway is connected to defective copper homeostasis.
Juan Antonio Navarro, a biochemist at Regensburg University in Germany, says the approach of using genealogical proteomics is interesting because it offers a new technique for applying insights gleaned from a rare disease to one that’s more common. “I think that this is a double impact,” he says.