New research from the US finds the action of three gene variants already linked with Parkinson’s may contribute to a defect in how brain cells move internal proteins around. The discovery could help explain the cause of, and point to treatment for, the common, non-familial form of the disease.
The researchers, from Columbia University Medical Center (CUMC) in New York, write about their findings in the 6 February issue of Neuron.
Most people with Parkinson’s disease have the sporadic, non-familial form of the disease, with a small proportion having familial Parkinson’s, or the form that can be attributed to known genetic factors.
Now CUMC researchers have identified a defect in a pathway in brain cells that may underlie the common, non-familial form of the disease.
The defect is in a pathway known as the “retromer” pathway, because it guides the recycling of key proteins by moving them back from the surface of the cell to its internal stores.
The researchers found that defects in this pathway may disrupt the ability of cells to dispose of unwanted proteins, which may explain why brain cells of people with Parkinson’s accumulate clumps of protein.
They suggest the defects can be reversed by increasing pathway activity, offering a possible route to treatment. There are currently no treatments that alter progression of Parkinson’s.
The researchers found that the actions of at least three different genes, mutations of which have already been linked to Parkinson’s disease in other studies, converge on this pathway.
They also found evidence that the molecular changes behind the defects in the retromer pathways are present in people without Parkinson’s but who carry gene variants linked to increase risk of the disease.
They suggest this supports the idea that early treatment will be an important approach to tackling the disease.
Senior author Asa Abeliovich, associate professor of pathology and cell biology and of neurology at CUMC’s Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, says in a statement:
“Taken together, the findings suggest that drugs that target the retromer pathway could help prevent or treat Parkinson’s.”
With the aid of new techonologies like genome-wide association studies (GWAS), scientists have now found nearly a dozen common gene variants linked to non-familial Parkinson’s. Each appears to have only a small effect on risk, but it is not easy to get a clear picture of how they may contribute to the disease because you can’t just open the brains of people in early stages of the disease and have a look.
However, the problem with the only option that remains, which is to examine the brains of people with Parkinson’s after they have died is, as Abeliovich, explains, “it’s usually too late – all the critical dopamine neurons are long gone and the damage has been done”.
So for their study, Abeliovich and colleagues used a novel approach that brought together human functional genomics with culture studies of brain neurons and animal model studies (including fruit fly models that contain genetic variants related to those associated with Parkinson’s disease).
They found that common variants in LRRK2 and RAB7L1, two genes already tied to Parkinson’s, had an unexpected similar effect on human brain tissue.
The two genes appeared to have a common route of action. The researchers observed prominent cellular changes in the retromer pathway, which guides the transport of proteins from the Golgi apparatus to the lysosomes. The Golgi apparatus is where proteins are packaged, ready for delivery to other parts of the cell, and the lysosomes are where proteins and other molecules are broken down and recycled.
The researchers also showed that over-expression of RAB7L1 can overcome the effect of the other variant, LRRK2.
Similarly, expression of a variant of a third gene VPS35, that is also involved in the retromer pathway, can suppress LRRK2.
Abeliovich says it would be interesting to see if drugs can be found that “directly target these retromer components or that more generally promote flow through the pathway”.
The researchers point out that some people with familial Parkinson’s disease also carry gene mutations that affect the retromer pathway.
Also, earlier studies at CUMC’s Taub Institute have shown that variants in retromer-associated genes are linked to Alzheimer’s disease, and that cells from brains of people who died with Alzheimer’s disease appear to have defects in retromer components.
Abeliovich says all this evidence suggests defective retromer functioning may play a broader role in neurodegenerative diseases of aging.
Funds from the Michael J. Fox Foundation and the National Institutes of Health helped finance the study.
Written by Catharine Paddock PhD