Two early-career Einstein neuroscientists have received significant and prestigious grants to support their research into Parkinson’s disease (PD) and opioid use disorder.
Frank Soldner, M.D., assistant professor in the Dominick P. Purpura Department of Neuroscience and in the department of genetics at Einstein, will receive $1.6 million over three years as part of an interdisciplinary research team that will share a $6.8 million grant awarded by the Aligning Science Across Parkinson’s (ASAP) initiative. The five-member team is led by Donald Rio, Ph.D., at University of California, Berkeley.
PD involves the unexplained die-off of brain cells that produce dopamine, the neurotransmitter vital for coordinating movement. Dr. Soldner and team members at UC Berkeley and UC San Francisco will study the role played by genes associated with PD.
Until about 25 years ago, PD was not thought to have a genetic connection. That changed in 1997, when National Institutes of Health scientists found that mutations in the SNCA gene were common in several families in which many members had PD.
Today, at least 15 hereditary PD risk genes have been identified, accounting for some 10 percent of PD cases. More than 90 additional regions of the genome have been implicated in the remaining 90 percent so-called sporadic cases of PD. Those additional gene variants are not sufficient to cause the disorder on their own but are thought to substantially increase the risk that people will develop PD. Dr. Soldner and his team will study both types of PD genes.
CRISPR-Cas9 gene editing will be used to introduce each of the known hereditary gene mutations into human pluripotent stem cells. Those stem cells will be coaxed to develop into brain-like organoids, often referred to as “mini brains,” which contain thousands of dopamine-producing neurons. The researchers want to see how familial mutations affect the neurons—in particular, how they influence levels and types of messenger RNA.
As for the more than 90 gene variants associated with sporadic PD, Dr. Soldner and colleagues will use CRISPR-Cas9 to activate or inhibit them to identify common differences between familial and sporadic forms of PD and see whether, and how, those gene variants interact with familial PD mutations in the same cell. The scientists hope to find genes or intracellular pathways that can be targeted by drugs.
Lucas Sjulson, M.D., Ph.D., assistant professor in the department of psychiatry and behavioral sciences and the Dominick P. Purpura Department of Neuroscience, has received a five-year, $2.5 million National Institutes of Health Director’s Pioneer Award from the National Institute on Drug Abuse (NIDA). Dr. Sjulson is one of only five recipients of grants from NIDA’s Avenir Award Program for Genetics or Epigenetics of Substance Use Disorders, which are given to early-stage investigators who propose highly innovative studies.
Opioid addiction has reached epidemic levels in the United States. Data from 2018 shows that 128 people die each day in the United States due to overdosing on opioids, according to the U.S. Centers for Disease Control and Prevention. Some effective therapies exist, but new treatments are urgently needed.
Recent advances in single-cell analysis have revealed many different neuron subtypes in the brain—which poses a challenge for understanding the brain’s involvement in opioid addiction. The goal of Dr. Sjulson’s project is to understand how distinct subtypes of brain neurons interact to influence opioid use disorder.
Dr. Sjulson will use innovative optogenetic and electrophysiological techniques to record neuronal activity of genetically distinct brain cells in mice, while the animals are self-administering oral opioids. He will focus on cells of the nucleus accumbens—a part of the brain’s reward system that plays an important role in addiction.
Dr. Sjulson will also analyze different types of brain neurons using other techniques, including: epigenomic studies, to see how cell types differ with respect to chemical compounds that affect gene expression; single-cell transcriptomics, which can assess the gene-expression levels of individual neurons by measuring the messenger RNA levels of thousands of genes; and advanced in vivo multiphoton imaging, which provides insight into cellular processes by imaging individual cells deep within living tissue.
Understanding the relationships among different cell types in the nucleus accumbens may provide insights into the neural basis of drug addiction and lead to treatments for targeting cell types responsible for addiction and relapse.
Posted on: Wednesday, October 28, 2020