Neuron Archives - Sanford Burnham Prebys
Institute News

Using stem cells to study the biochemistry of learning

AuthorMiles Martin
Date

August 18, 2022

A method for studying human neurons could help researchers develop approaches for treating Alzheimer’s, schizophrenia and other neurological diseases

Researchers from the Conrad Prebys Center for Chemical Genomics have developed a procedure to use neurons derived from human stem cells to study the biological processes that control learning and memory. The method, described in Stem Cell Reports, uses electrodes to measure the activity of neuronal networks grown from human-induced pluripotent stem cells (iPSCs). The procedure tracks how synapses—the connections between neurons—strengthen over time, a process called long-term potentiation (LTP).

“Impaired long-term potentiation is thought to be central to many neurological diseases, including Alzheimer’s, addiction and schizophrenia,” says senior author Anne Bang, PhD, director of Cell Biology at the Prebys Center. “We’ve developed an approach to study this process in human cells much more efficiently than current methods, which could help trigger future breakthroughs for researchers working on these diseases.”

LTP helps our brain encode information, which is what makes it so critical for learning and memory. Impairment of LTP is thought to contribute to neurological diseases, but it has proven difficult to verify this hypothesis in human cells.

LTP helps our brain encode information, which is what makes it so critical for learning and memory. Impairment of LTP is thought to contribute to neurological diseases, but it has proven difficult to verify this hypothesis in human cells.

Anne Bang, PhD, director of Cell Biology at the Prebys Center.

“LTP is such a fundamental process,” says Bang. “But the human brain is hard to study directly because it’s so inaccessible. Using neurons derived from human stem cells helps us work around that.”

Although LTP can be studied in animals, these studies can’t easily account for some of the more human nuances of neurological diseases.

“A powerful aspect of human stem cell technology is that it allows us to study neurons produced from patient stem cells. Using human cells with human genetics is important in these types of tests because many neurological diseases have complex genetics underpinning them, and it’s rarely just one or two genes that influence a disease,” adds Bang.

To develop the method, first author and Prebys Center staff scientist Deborah Pré, PhD, grew networks of neurons from healthy human stem cells, added chemicals known to initiate LTP and then used electrodes to monitor changes in neuronal activity that occurred throughout the process.

The method can run 48 tests at once, and neurons continue to exhibit LTP up to 72 hours after the start of the experiment. These are distinct advantages over other approaches, which can often only observe parts of the process and are low throughput, which can make getting results more time consuming.

For this study, the researchers used neurons grown from healthy stem cells to establish a baseline understanding of LTP. The next step is to use the approach on neurons derived from patient-derived stem cells and compare these results to the baseline to see how neurological diseases influence the LTP process.

“This is an efficient method for interrogating human stem cell–derived neurons,” says Bang. “Doing these tests with patient cells could open doors for researchers to discover new ways of treating neurological diseases.”

Institute News

Protecting motor neurons

AuthorSusan Gammon
Date

July 30, 2018

Neurodegenerative diseases are a major worldwide health problem, and researchers are hunting new strategies to combat them. One approach is to find the mutations that cause these diseases and design therapies to counteract them. But scientists can also pursue another strategy—identify molecules that protect neurons from harm.

SBP’s Laszlo Nagy, MD, PhD, may have found one of these. Nagy is working on gene regulation and epigenomics—so neurons are not his primary beat. But in a recent study published in The Journal of Neuroscience, he and colleagues have shown that the enzyme PRMT8 can protect aging motor neurons from stress, which could have therapeutic implications.

“We stumbled on this molecule PRMT8, which is a protein methyltransferase (an enzyme that adds methyl molecules to control protein expression and activity) while studying stem cell differentiation,” says Nagy. “When the molecule is not there, the motor neurons are less stress resistant. They are vulnerable to changes in their inner circuitry, including DNA damage, and they eventually die.”

Stress management is particularly important in motor neurons, which connect the central nervous system to muscles. Mature motor neurons cannot divide anymore and must live a long time. Once they die, they are lost forever.

In the study, the lab found that motor neurons in animals without PRMT8 developed a number of issues. The cells had DNA breaks and other problems that slowly killed them off. As motor neurons died, the animals gradually lost muscle strength.

“In older animals, they were having difficulty coordinating their movements,” says Nagy.

Because PRMT8 has the potential to protect motor neurons, it could be a compelling drug target. Boosting the enzyme could help slow a number of neurodegenerative conditions, including  ALS. In addition, because the enzyme is only found in the central nervous system, it offers a selective target. This is particularly important, since adding stress protection to dividing cells could cause cancer.

Now that they have identified PRMT8’s neuroprotective benefits, Nagy and colleagues are taking the next step—looking for agents that could make the enzyme more active and potentially help motor neurons resist disease and live longer.

“We’re trying to identify a small molecule that would enhance PRMT8, so we could specifically modulate its activity,” he says.

Institute News

How protein tangles accumulate in the brain and cause neurological disorders

Authorsgammon
Date

September 2, 2015

A new Sanford Burnham Prebys Medical Discovery Institute (SBP) study takes a step forward in understanding how similar, yet genetically unrelated neurodegenerative diseases, such as Alzheimer’s disease, frontal temporal dementia, and progressive supranuclear palsy (PSP) are caused by the protein tau. The findings, published today in Neuron, create new opportunities to target this key protein that leads to the brain lesions found in patients with impaired motor functions and dementia. Continue reading “How protein tangles accumulate in the brain and cause neurological disorders”