A mutation in a protein-sorting gene is linked with Parkinson's disease

July 14, 2011, Cell Press

Parkinson disease (PD) is a devastating incurable disease in which degeneration of dopamine neurons in the brainstem leads to tremors and problems with movement and coordination. An increasing proportion of patients appear to be genetically predisposed to disease. Now, two independent research groups have identified a mutation associated with an inherited form of PD. The papers, published by Cell Press in the July 9 issue of The American Journal of Human Genetics, provide new insight into the pathogenesis of late-onset PD and present compelling evidence that implicates a novel protein-recycling pathway in neurodegeneration.

"Previous studies of familial parkinsonism have identified pathogenic mutations in several genes, providing mechanistic insight and novel targets for ," say the lead authors of one of the studies, Dr. Carles Vilariño-Güell and Dr. Matthew J. Farrer from the University of British Columbia. "In our study, we identified a pathogenic mutation associated with PD in a Swiss family where multiple individuals presented with disease. Confirmation of the discovery was an international effort embraced by neurologists in Canada, Israel, Norway, Switzerland, Taiwan, Tunisia, and the United States."

A second independent study, led by Dr. Tim M. Strom from the Institute of Human Genetics in Neuherberg, Germany and Dr. Alexander Zimprich from the Medical University of Vienna, used the same sophisticated sequencing techniques to look for causal mutations in a family from Austria with multiple incidences of late-onset PD.

Both groups discovered the same mutation in the vacuolar protein-sorting-associated protein 35 (VPS35) gene in affected family members. The VPS35 protein is part of a complex called the "retromer" that mediates the intracellular transport and sorting of membrane-associated cell-surface proteins that are going to be recycled or destroyed. "A single variant in the VPS35 gene was found in all affected family members investigated, was absent in general population samples, and was detected in two additional PD families," say Dr. Strom and Dr. Zimprich.

Taken together, the findings suggest that the VPS35 mutation is the genetic determinant of the late-onset PD examined in the studies and that perturbation of retromer-mediated protein sorting is linked with neurodegeneration. Interestingly, recent studies have suggested that retromer sorting defects are also associated with Alzheimer disease.

"Screening of VPS35 and its interacting partners, not only in PD patients but in other movement and cognitive disorders, is warranted to fully understand the role of the retromer in disease development. However, it is unclear how mutant VPS35 impairs retromer function or the transport of specific cargos or why dopaminergic are selectively vulnerable," concludes Dr. Farrer's team. "Model systems based on VPS35 can now focus on these issues and will facilitate the development of novel therapeutics."

Related Stories

Recommended for you

How incurable mitochondrial diseases strike previously unaffected families

January 15, 2018
Researchers have shown for the first time how children can inherit a severe - potentially fatal - mitochondrial disease from a healthy mother. The study, led by researchers from the MRC Mitochondrial Biology Unit at the University ...

Genes that aid spinal cord healing in lamprey also present in humans

January 15, 2018
Many of the genes involved in natural repair of the injured spinal cord of the lamprey are also active in the repair of the peripheral nervous system in mammals, according to a study by a collaborative group of scientists ...

The coming of age of gene therapy: A review of the past and path forward

January 11, 2018
After three decades of hopes tempered by setbacks, gene therapy—the process of treating a disease by modifying a person's DNA—is no longer the future of medicine, but is part of the present-day clinical treatment toolkit. ...

Large-scale study to pinpoint genes linked to obesity

January 10, 2018
It's not just diet and physical activity; your genes also determine how easily you lose or gain weight. In a study published in the January issue of Nature Genetics, researchers at the Icahn School of Medicine at Mount Sinai ...

Identical twins can share more than identical genes

January 9, 2018
An international group of researchers has discovered a new phenomenon that occurs in identical twins: independent of their identical genes, they share an additional level of molecular similarity that influences their biological ...

Hereditary facial features could be strongly influenced by a single gene variant, a new study finds

January 9, 2018
Do you have your grandmother's eyes? Or your father's nose? A new study by the Universities of Oxford and Surrey has uncovered variations in singular genes that have a large impact on human facial features, paving the way ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.