Two new grants totaling nearly $14 million over three years will jump-start research at UC Berkeley into the molecular and genetic causes of Parkinson’s disease, a neurodegenerative disorder that afflicts more than 1 million Americans, yet whose cause remains a mystery.
The grants are among 21, for a total of $161 million, announced today by the Aligning Science Across Parkinson’s (ASAP) initiative, which hopes to close gaps in our understanding of the basic mechanisms of the disease and its progression. The ASAP has received substantial philanthropic support and is partnering with the Michael J. Fox Foundation to administer the program.
Image credit: HKB-Interpretation via Wikimedia (CC BY-SA 4.0)
Parkinson’s disease is characterized by tremor, slowness, stiffness and problems with walking and balance that often progress slowly for decades. In some people, it can be accompanied by memory problems, depression, constipation and other symptoms not related to movement.
While drugs that mimic dopamine alleviate some symptoms — though often for only four to seven years — they don’t halt the progression of the disease, and there is no way to predict how the disease will progress and how quickly.
And while there are many intriguing new findings — some 20 genes are implicated in Parkinson’s, and new ideas have emerged about what is responsible for killing off brain cells that produce dopamine, a neurotransmitter key to coordinating movement — they are like pieces of a puzzle that no one yet knows how to fit together, said Randy Schekman, a Nobel laureate, UC Berkeley professor of molecular and cell biology and scientific director of ASAP.
“The disease presents in different ways, and it progresses in different ways,” said Schekman, whose wife died three years ago of Parkinson’s after 20 years of slow decline. “There is no way to know — this was really the most frustrating thing for me. No one could tell me with any certainty how my wife’s illness would progress, what to expect next. It is very idiosyncratic.”
“The hope is that, by finding some biomarker or markers, you would be able to chart a path forward to know where things were headed for patients as you can with cancer or heart disease,” he added.
While billions of dollars have been invested over the years in Parkinson’s research by the National Institutes of Health (NIH), the Michael J. Fox Foundation and other private funders, much of that has gone into clinical studies, Schekman said.
“The NIH has a very strong push for clinical relevance. The position of ASAP is that we want people who are working on something that is relevant to Parkinson’s, but we are not funding clinical research at all, we are not funding drug discovery. We are funding basic science,” he said.
The new UC Berkeley grants — $6.8 million to a team led by Donald Rio and $7 million to a team led by James Hurley — involve researchers at UC Berkeley and other universities, in keeping with ASAP’s focus on interdisciplinary teams as the key to basic research advancements.
“For a tough problem like Parkinson’s, a disease that has been recognized for, now, 200 years, my feeling is we need to find a way to get people to collaborate more intensely than they usually do,” Schekman said. “That is our premise. Our niche is the idea that really meaningful team science will make a difference.”
Mitochondrial damage
Hurley’s team will investigate the role of damaged mitochondria — the energy powerhouses of the cell — in causing the death of dopamine neurons in the brain. The team includes Eunyong Park, assistant professor of molecular and cell biology at UC Berkeley, Erika Holzbaur of the University of Pennsylvania, Sascha Martens of the Max Perutz Labs in Austria and Michael Lazarou of Monash University in Australia.
According to Hurley, one of the most promising leads in Parkinson’s research today involves two genes, PINK1 and Parkin, mutated variants of which are found in families with the hereditary form of the disease. Richard Youle at the NIH this week received the 2021 Breakthrough Prize for establishing what these normal and mutated genes do: They are responsible for labelling damaged mitochondria for recycling, a process called mitophagy. When the genes are mutated, damaged mitochondria accumulate, fall apart and release their DNA, which causes cellular inflammation and eventual cell death of the neurons that produce dopamine.
Hurley has studied cellular recycling, called autophagy, for more than 10 years and will employ the techniques he has developed to study the entire process of mitophagy, in collaboration with established Parkinson’s researchers Holzbaur and Lazarou, who has worked with Youle.
“The Parkin and PINK1 genes have been more specifically tied to mitophagy than any of the other genes associated with the disease,” said Hurley, professor of molecular and cell biology and a faculty affiliate at Berkeley Lab. “That is the reason we are going to dive deep and really work out in great, gory detail, atom by atom, exactly how the genes affect mitophagy at the level of precision that we would need to compute what steps you would have to change, and by how much, in a therapy. And while this is a basic science project and not drug discovery, a spin-off of the project will be the molecular structures you would dock drugs to, in order to cure it.”
Building mutated organoids
Rio’s team includes Dirk Hockemeyer and Helen Bateup — associate professor and assistant professor, respectively, of molecular and cell biology at UC Berkeley — Frank Soldner from Albert Einstein College of Medicine in New York and Luke Gilbert from UCSF. They will focus on understanding the 20 familial or hereditary Parkinson’s risk genes and more than 300 other regions of the genome implicated in the disease.
Using CRISPR-Cas9 genome editing, the team will engineer the 20 known hereditary mutations in human pluripotent stem cells and then coax those stem cells to become dopaminergic neurons and grow into organoids with thousands of cells. They hope to see what impact these mutations have on the cells — in particular, the levels and forms of messenger RNA, which is Rio’s speciality.
The other 320 regions of the human genome have been associated with sporadic Parkinson’s from whole-genome sequencing of patient samples. More than about 90% of Parkinson’s cases are sporadic — random occurrences of the disease without any hereditary component. The team will use CRISPR interference to down-regulate those regions in single cells to test for genetic interactions with the familial Parkinson’s mutations.
Once the biologic effects of these Parkinson’s-associated genes are known, the researchers hope to find biomarkers of Parkinson’s and perhaps identify genes or cellular pathways that could be targeted by drugs.
“I am excited about the possibility that, if we find something, there might be a reasonable chance that we will find small molecule drugs that would affect RNA processing or gene expression, in general, which we could test in the organoids,” Rio said.
Rio noted that the size of these grants, which is far above what most funding agencies, public or private, typically provide, and the intensive collaborative team effort will be key to the success of these projects.
“Manipulating, modifying and differentiating human pluripotent stem cells is a very expensive endeavour,” he said. “ASAP is funding these projects at a level that we would never be funded for by the federal government. The people involved in this project are going to be able to do a lot in a pretty short time because the funding has been very generous. It is really quite exceptional.”
Source: UC Berkeley