Tiny changes in DNA that have been linked to Parkinson鈥檚, the second most common neurodegenerative disorder after Alzheimer鈥檚, were found not only in brain cells, where they were expected, but also in liver, fat, immune and developmental cells. These findings may one day contribute to the development of preventative interventions before the disease鈥檚 effects become pronounced.
鈥淲hen we looked at the data, we were quite surprised to see the variation in tissue types,鈥� said , a professor at Van Andel Research Institute (VARI) and the study鈥檚 corresponding author. 鈥淯ltimately, if we can more precisely define risk factors for Parkinson鈥檚, we can develop ways to mitigate them early on. We still have a long way to go but these findings are some of the first steps down that path.鈥�
A cumulative effectAlthough these changes, called single-nucleotide polymorphisms (SNPs), are very small, an accumulation of enough SNPs can significantly heighten a person鈥檚 risk for developing Parkinson鈥檚. It can be likened to dropping sand onto a scale鈥攁 single grain will have little effect, but if enough grains are added, the balance will tip.
The human genome contains about 80 million SNPs, many of them located in regions of the DNA that were once thought to be junk. Scientists now know that these areas, located outside of genes on the DNA, play critical roles in regulating gene expression and are a useful tool for matching a particular gene with its function or role in disease.
As such, investigating SNPs linked to Parkinson鈥檚 offers a unique opportunity to answer one of the major questions in Parkinson鈥檚 research鈥攚hat causes or contributes to the disease? While scientists know that five to 10 percent of Parkinson鈥檚 cases are passed down genetically through families, they鈥檙e still determining what鈥檚 behind the majority of cases. The prevailing theory is a mix of genetic and environmental factors create a perfect storm, leading to the hallmark clumping of abnormal proteins that spread through the brain, killing cells that produce a chemical called dopamine that is vital for voluntary movement.
Different tissues, common linkUsing information from the federally funded as a guide, Coetzee, the team at VARI and collaborators at Cedars-Sinai in Los Angeles analyzed 21 of these risk areas, called loci, in 77 cell types. Of these, the team found 12 loci across several tissue types that were particularly enriched鈥攐r full of SNPS鈥攊ndicating an increase in risk.
Intriguingly, only one locus was identified in the substantia nigra, the part of the brain where dopamine-producing neurons die. Other loci were found in liver, fat, immune and developmental cells. It is the first time this type of genome-wide analysis has been used to investigate Parkinson鈥檚 disease.
Although much more work must be done to unravel exactly how these loci affect risk, there are interesting parallels between the team鈥檚 findings and recent work done by others investigating Parkinson鈥檚. For example, three of the risk loci were found in immune cells, a promising finding as evidence suggests that Parkinson鈥檚 may be linked to inflammation, the immune system鈥檚 reaction to help fight off potential threats.
鈥淥nly a small percentage of Parkinson鈥檚 cases are familial and have a clear and well-defined genetic inheritance. The remaining cases develop the disease seemingly at random,鈥� said , director of VARI鈥檚 Center for Neurodegenerative Science and one of the study鈥檚 authors. 鈥淭he emerging view is that Parkinson鈥檚 is more of a syndrome鈥攁 defined set of clinical symptoms and some shared features of brain pathology鈥攚ith a diverse set of underlying causes. One surprising finding in our study is that only one gene locus was clearly linked to the brain while others were associated with tissues throughout the body. This supports the emerging theory that Parkinson鈥檚 is a disorder that can be caused by disruptions in cellular processes in many locations, not just one. Furthermore, for the disease to develop in one person there has to be an unfortunate combination of a genetic predisposition and, as yet undefined, environmental insults.鈥�
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This work was supported by funding from Van Andel Research Institute and Cedars-Sinai.
What is Parkinson鈥檚?
Parkinson鈥檚 disease is a progressive neurological disease marked by tremor, rigidity and loss of voluntary movement, among other non-motor symptoms. Between seven and 10 million people globally have the disease. Of those, the majority of cases have no known cause although scientist suspect a mix of genetic, epigenetic and environmental factors.
What is a SNP?
DNA is like a ladder, with the rungs being pairs of molecules called nucleotides. Single-nucleotide polymorphisms, or SNPs, are variations in one of these nucleotides at a specific point on DNA. Although SNPs are extremely useful tools in finding genes linked to diseases, it can be very difficult to make these connections as SNPs can be located far away on the genome from the gene they affect.
What are genome-wide association studies?
Genome-wide association studies (GWAS) compare the genomes of a healthy control group to a test group, for example people with Parkinson鈥檚, to see where there are differences in their genetic makeup.
ABOUT VAN ANDEL RESEARCH INSTITUTEVan Andel Institute (VAI) is an independent nonprofit biomedical research and science education organization committed to improving the health and enhancing the lives of current and future generations. Established by Jay and Betty Van Andel in 1996 in Grand Rapids, Michigan, VAI has grown into a premier research and educational institution that supports the work of more than 360 scientists, educators and staff. ), VAI鈥檚 research division, is dedicated to determining the epigenetic, genetic, molecular and cellular origins of cancer, Parkinson鈥檚 and other diseases and translating those findings into effective therapies. The Institute鈥檚 scientists work in onsite laboratories and participate in collaborative partnerships that span the globe. 100% To Research, Discovery & Hope庐
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