A recent study suggests that a genetic mutation that disrupts a protein involved in the degradation of biological material within neurons allows waste products to accumulate, contributing to the pathology of Parkinson’s disease. Mutations in this protein, Vps35, have been associated with Parkinson’s disease, but until now, it was not clear how they could contribute to the development of the disease.
The study, “Parkinson’s Disease Linked Vps35 R524W Mutation Impairs The Endosomal Association Of Retromer And Induces Α-Synuclein Aggregation,” was published by Jordan Follett and colleagues from the University of Queensland in Australia in the Journal of Biological Chemistry.
“It has been identified that one of these proteins (Vps35) is mutated in some Parkinson’s patients, which creates congestion in the transport network inside cells,” Rohan Teasdale, the study’s lead author, said in a news release.
“As a result, it appears that the workers responsible for recycling material within these neurons are not getting to their correct workplace, and without their assistance the cells within the brain cannot rid themselves of waste materials, which increases the likelihood of cell death. It’s this cell death that then causes the symptoms of Parkinson’s disease, such as tremors and muscle stiffness.”
In their study, the researchers introduced two mutated versions of the Vps35 protein — Vps35 P316S and Vps35 R524W — both of which had been identified in patients with Parkinson’s disease, and analyzed their impact on cell functioning. The normal form of Vps35 interacts with the machinery that regulates the trafficking of materials within cells and allows material that’s no longer needed to be sent for degradation in specialized compartments in the cell.
However, the dysfunctional Vps35 R524W form (but not Vps35 P316S) was poorly able to maintain its function, thereby contributing to the impairment of the recycling and cleaning abilities of the cells and promoting the accumulation of waste. One of the molecules that accumulated within cells was alpha-synuclein, a protein that is known to form large accumulations of aggregates in a brain with Parkinson’s disease, impairing neuronal function.
The results indicate that, by slowing or stopping the trafficking of alpha-synuclein and other molecules to the “garbage bins” within cells, mutated Vsp35 contributes to the accumulation of molecules that are linked to the development of Parkinson’s disease.
“As part of this study we expanded the transport network within these cells which reinstated traffic flow so the neurons could rid themselves of waste,” Teasdale said. “We believe that expanding the cells’ recycling capacity could halt or drastically slow the progression of the disease.”
In addition to Parkinson’s disease, other diseases triggered by the accumulation of waste materials in the cells (called lysosomal diseases) can benefit from future therapies targeting this recycling mechanism.