An international team of scientists from the University of Bristol, University of Texas Southwestern Medical Center, and the Mayo Clinic believe they have taken a step closer to unraveling the causes of Parkinson’s disease. They report that they have shown that a specific mutation impairs the ability to transport proteins correctly within cells.

Being starved of these proteins could be part of why the body loses nerve cells in the part of the brain responsible for producing the chemical dopamine which helps control and coordinate body movements. A mutation in the VPS35 gene is known to be linked to Parkinson's disease, but experts have not been able to pinpoint its role until now.

The current study, entitled “Retromer Binding to FAM21 and the WASH Complex Is Perturbed by the Parkinson Disease-Linked VPS35(D620N) Mutation,” published in Current Biology, reveals that the VPS35 mutation impairs the cell's ability to transport a subset of cargo proteins to their correct destinations.

They also identified three additional proteins affected by this mutation, some of which are already linked with Parkinson's disease.

“We established that in cells expressing VPS35(D620N) there is a perturbation in endosome-to-TGN transport but not endosome-to-plasma membrane recycling, which we confirm in patient cells harboring the VPS35(D620N) mutation. Through comparative stable isotope labeling by amino acids in cell culture (SILAC)-based analysis of wild-type VPS35 versus the VPS35(D620N) mutant interactomes, we establish that the major defect of the D620N mutation lies in the association to the actin-nucleating Wiskott-Aldrich syndrome and SCAR homolog (WASH) complex,” wrote the investigators. “Moreover, using isothermal calorimetry, we establish that the primary defect of the VPS35(D620N) mutant is a 2.2 ± 0.5-fold decrease in affinity for the WASH complex component FAM21. These data define the primary molecular defect in retromer assembly that arises from the VPS35(D620N) mutation and, by revealing functional effects on retromer-mediated endosome-to-TGN transport, provide new insight into retromer deregulation in Parkinson disease.”

“The discovery of the molecular defect associated with the VPS35 mutation offers a potentially exciting avenue of research into the causes of this disease,” explained Peter Cullen, Ph.D., from the school of biochemistry at the University of Bristol. “This research significantly adds to the growing body of evidence that the retromer complex, which VPS35 is a part of, is a potential therapeutic target when designing drugs to help combat this and other neurodegenerative diseases.”

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