Dr. Patrik Brundin, the Jay Van Andel Endowed Chair in Parkinson's Research at Van Andel Research Institute. Courtesy VAI
A Van Andel Institute researcher studying Parkinson’s disease has co-authored a report, detailing, for the first time, how the disease spreads through the brain via a protein — and uncovering a trail for possible drug development to slow symptoms.
The protein, α-synuclein — misfolded in Parkinson’s disease patients — spreads from parts of the brain connected to the nose to other brain regions that become affected by the disease.
“A major unmet medical need is a therapy that slows disease progression,” said Dr. Patrik Brundin, a VAI researcher. “We hope an understanding of how α-synuclein moves between brain regions will help uncover molecules that we can target with new drugs to slow the progression of symptoms in patients.”
Brundin, who has held the Jay Van Andel Endowed Chair in Parkinson's Research at Van Andel Research Institute in Grand Rapids since early 2012, is head of the Neuronal Survival Unit at Lund University in Sweden and senior author of the study.
The new research is particularly important in the context of previous work, suggesting that, in people who are destined to eventually develop Parkinson’s disease, the large aggregates composed mainly of the α-synuclein protein develop and appear progressively in different brain regions, according to a VAI announcement. The spread seems to follow a set pattern affecting certain brain regions, such as the nose and the gut early in the disease and others later.
Parkinson’s strikes more than 1 percent of people over 65 and is the second most common neurodegenerative disorder after Alzheimer’s disease, according to VAI.
The researchers focused on the olfactory bulb, part of the brain involved in the perception of odors. A poor sense of smell is among the very first symptoms appearing in Parkinson’s disease, often several years before the patients experience problems with movement.
The research team based their strategy on the hypothesis that the spread of a misfolded protein known as α-synuclein, which forms large aggregates in the brain of patients, is a crucial component of the development of the disease.
The study, “Transfer of human α-synuclein from the olfactory bulb to interconnected brain regions in mice,” was published this month in the journal Acta Neuropathologica and demonstrates, for the first time, that α-synuclein injected into the olfactory bulb is taken up by neurons and transferred to interconnected regions of the brain in mice and the form of α-synuclein dramatically affects the process.
Scientists conducted several experiments injecting different molecular species, of varying sizes and shapes, of human α-synuclein into the olfactory bulbs of mice. They found that the protein is taken up very quickly by neurons in the olfactory bulb. Then, within minutes to hours, the injected protein is also found in neurons in structures connected to the olfactory bulb. This ability to undergo rapid transport between brain regions seems to be a characteristic feature of the α-synuclein protein.
Nolwen L. Rey, a Postdoctoral Fellow at the Neuronal Survival Unit, Lund University, is first author of the study, and he will be joining the staff at VAI in early 2014. Research was also done by Laboratoire d’Enzymologie et de Biochimie Structurale, CNRS, Gif-sur-Yvette, France.
“The transfer to interconnected regions supports the idea that α-synuclein can transfer effectively along neural pathways and, thereby, can contribute to the progression of the α-synuclein-related pathology,” Rey said. “After transfer, in young healthy mice, the injected proteins were gradually removed by the nerve cells. But we believe that when cellular mechanisms that protect against misfolded proteins fail, the misfolded α-synuclein could stay and trigger the formation of large protein aggregates that eventually impair or kill the cells.”
Van Andel Research Institute, VAI’s research arm, is dedicated to studying the genetic, cellular and molecular origins of cancer, Parkinson’s and other diseases and working to translate those findings into effective therapies.
The staff includes more than 200 researchers in on-site laboratories and in collaborative partnerships around the globe.
Jay Van Andel, a founder of Amway and the founder of the VAI, died from the effects of Parkinson’s in 2004.