Neurology Today: 18 May 2017 - Volume 17 - Issue 10 - p 53–54
THE RESEARCHERS want to explore the notion that multiple genetic lesions within the group of genes might contribute to an accumulated risk for Parkinson's disease.
Researchers reported that patients with Parkinson's disease have a significant burden of variants among 54 genes known to be linked to lysosomal storage disorders, compared to controls. They said the finding represents new insight into the origins of the disease, which could shape future research and treatment.
BOSTON—Gene variants linked to lysosomal storage disorders predispose people to Parkinson's disease (PD), according to an analysis of a large, whole-exome sequencing dataset presented here at the AAN Annual Meeting in April.
Researchers found from whole exome sequencing data in over 2,900 subjects that patients with PD have a significant burden of variants among 54 genes known to be linked to lysosomal storage disorders, compared to controls. They said the finding represents new insight into the origins of the disease, which could shape future research and treatment. The link was also replicated using two independent cohorts.
“The gene set points to some very clear biology that could be targeted for further mechanistic investigation and therapy — the lysosome — which may be more important than any specific gene that is implicated here,” said Joshua Shulman, MD, PhD, assistant professor of neurology at Baylor College of Medicine in Houston, TX, who jointly led the study with Peter Heutink, PhD, a group leader at the German Center for Neurodegenerative Diseases in Tübingen, Germany.
Researchers suspect that dysfunctional lysosomes, which digest material that cells no longer need, play a role in PD. Glucocerebrosidase (GBA) and sphingomyelin phosphodiesterase 1 (SMPD1), both of which are lysosomal disorder storage disorder genes, have been found to be associated with a heightened risk of PD.
GBA causes Gaucher's disease, in which patients develop an enlarged liver and spleen; it usually does not have neurologic symptoms. SMPD1 predisposes people to Niemann-Pick's disease, which has wide-ranging effects, including cognitive and motor dysfunction.
“It was a bit of a surprise when previous researchers found that individuals who have Gaucher's disease are at a higher risk of Parkinson's disease,” said lead author Laurie Robak, MD, PhD, instructor of molecular and human genetics at Baylor, who presented the new findings at the AAN Annual Meeting. The predisposition for PD is for anyone with a GBA variant, whether or not they have Gaucher's, she noted.
“We propose an oligogenic model of PD, in which multiple genetic hits may act in combination to degrade lysosomal function, enhancing disease susceptibility.”
he innovation in this analysis, Dr. Shulman said, was to look more broadly. For that, they collaborated with the International Parkinson's Disease Genomics Consortium, which has obtained whole-exome sequencing for about 1,200 PD patients and about 1,500 controls. It's thought to be the largest whole-exome sequencing cohort in PD currently available.
|DR. LAURIE ROBACK: “We propose an oligogenic model of PD, in which multiple genetic hits may act in combination to degrade lysosomal function, enhancing disease susceptibility.”|
“The innovation here is looking at the genes as a group rather than trying to look singly at each specific gene,” Dr. Shulman said, although the group did also confirm the association of both GBA and SMPD1 with PD, and found links between PD and three other genes.
He said his group is “very excited” to pursue “the idea that one might accumulate risk for Parkinson's disease by having multiple genetic lesions within the group of genes. Because in our cohort, we find that half of Parkinson's cases had at least one genetic variant predicted to be damaging, and about 20 percent of the cohort has two or more variants.”
Andrew S. Feigin, MD, associate professor of neurology and molecular medicine at Hofstra Northwell School of Medicine in Hempstead, NY, said the findings offer new insights to the pathophysiology of Parkinson's disease.
Figure. DR. JOSHUA SHULMAN: “The innovation here is looking at the genes as a group rather than trying to look singly at each specific gene.”
“This is an important study because it confirms something that people have suspected for a while — namely that the association of Gaucher's disease with PD is not unique, but is representative of a more general association of lysosomal storage disorders with PD,” he said.
That said, Dr. Feigin added that he doesn't expect the findings to have a clinical impact right away, though it could in the future.
“I do not see any immediate clinical relevance of this study, nor do I think there is a specific/individual genetic abnormality that is key — at least not as far as we know,” he said. “The importance of the finding is more related to the possibility that this may lead to a better understanding of the underlying causes of PD, which could lead to novel therapeutic approaches.”
Caroline M. Tanner, MD, PhD, FAAN, professor of neurology at the University of California, San Francisco, whose research has focused on the etiology of Parkinson's disease, said that these new findings on the lysosomal storage pathway could be especially powerful when coupled with the consideration of environmental factors implicated in PD.
“A lot of the work that I do is look at environmental and genome interaction in terms of Parkinson's etiology,” she said. “There is less mechanistic work that has been done, but the amount that (has been done) suggests that those same pathways are affected by environmental exposure. So, it's probably, for most people, going to be finding a lot of these little individual susceptibilities. And then, what happens to you in life? Are you exposed to certain chemicals? What are your behaviors? Do you exercise a lot or not? How does that modify [that susceptibility]? And how does it interact with other things like mitochondrial function that gives a full picture?”
This combination of factors will likely be the best way to assess a lot of patients, she said. “For the majority of people who don't have clear dominant gene, that's the etiology pathogenesis of Parkinson's disease. And so, I think that fits perfectly with that kind of an idea.”
She added, “I also think that there's a big take-home message about certain things that people can do if they do find they have lower risk — like exercise. That can't hurt and definitely can help.”
“We're still a little bit at the threshold,” she said. “It's still hard to put it all together. I think the evidence for these pathways has been accumulating over a decade or so. It's actually very exciting.”