Understanding Neurodegenerative Disease with Prion Research

ABOVE: Protein misfolding plays an important role in many neurodegenerative disorders. © istock.com, Eoneren

When Julie Moreno arrived at Texas A&M University as a first-generation student in 2000, she wanted to work in veterinary medicine. But the opportunity to work in a research laboratory during her time as an undergraduate ignited her passion for science and changed the course of her life. “Before that, I was never exposed to research,” said Moreno. “I didn’t even know it was an option.”

Once she had discovered this career path, she never looked back. After completing her undergraduate degree, she applied to a PhD program at Colorado State University (CSU), where her interest in neuroscience began to blossom.  “I love the brain,” she enthused. “It’s super exciting because there’s so many unknowns—like a big puzzle that we haven’t figured out yet.” 

In her graduate work, Moreno investigated the neurotoxic effects of manganese exposure on brain development, exploring the roles of glial cells and neuroinflammatory pathways in mediating these effects and identifying estrogen as a potential protective factor.^1,2 She impressed fellow lab members, including Katriana Popichak, an undergraduate researcher at the time, with her dedication to her research as well as her unflagging commitment to helping others. 

I love the brain…It’s super exciting because there’s so many unknowns—like a big puzzle that we haven’t figured out yet.

 —Julie Moreno, Colorado State University

Popichak, who now studies neuroinflammation and glial cell biology at CSU, said that Moreno played an important role in shaping her career. “She did amazing work,” said Popichak. “She was always so kind, and she really took me under her wing.”

After earning her doctorate, Moreno pursued a fellowship at the Medical Research Council Toxicology Unit with neuroscientist Giovanna Mallucci, where she was introduced to the fascinating field of prions. Prion diseases are characterized by abnormal folding of the host’s naturally-occurring prion protein, leading to rapid neurodegeneration. They can be genetic, sporadic—without known cause—or acquired, in which exposure to abnormal prion protein induces misfolding of the host’s own normal prion proteins. 

While prion disorders like Creutzfeldt-Jakob disease are vanishingly rare in humans, studying these conditions could provide important insights into more common diseases that involve protein misfolding and neurodegeneration. 

“What’s so cool about prions is that we’re able to address questions that we’re unable to address using mouse models of Alzheimer’s or Parkinson’s disease,” said Moreno. This is because mouse models of these neurodegenerative diseases usually involve genetic modification—overexpression or mutation of one gene (or set of genes) that mimics some of the underlying pathophysiology. While genetic factors can increase or decrease the risk of common neurodegenerative diseases in people, it is very rare for them to be genetically determined; for example, less than one percent of Alzheimer’s disease cases can be directly attributed to single gene mutations.³ 

A mouse that has been dosed with infectious prions on the other hand, is not really a model—it actually has prion disease, said Moreno. “They aren’t genetically modified to get the disease, which allows us to watch how this neurodegenerative disease naturally progresses, which is something we can’t do very well in these other laboratory models, although people are getting better at it.”

Historically, much of the research on neurodegenerative diseases involving abnormal protein aggregation, including rare prion diseases and the more common Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis (ALS), focused on strategies to prevent or clear these toxic protein clumps. This approach, while logical, has yet to yield highly effective human therapeutics. Moreno took a different approach during her time at the University of Cambridge: Instead of trying to prevent protein aggregation, she explored downstream interventions that could prevent aggregation-associated cell death.

         

Although the mechanisms of cell death are likely multifaceted, one important contributing pathway is the unfolded protein response (UPR). “The UPR is the normal cellular response to something that’s misshapen in the cell, and normally you want that to be turned on,” said Moreno. When activated acutely, the UPR is an adaptive response; it slows the synthesis of new proteins, reducing the protein folding load and alters many molecular and metabolic processes within the cell to restore homeostasis.⁴ However, said Moreno, when the UPR is chronically activated, the extended period of repressed translation means that the cell is unable to make proteins that are critical for synaptic function and cell survival. 

Moreno showed that targeting this pathway could be a viable strategy to prevent neuronal death in protein aggregation-related disorders. Inhibiting protein kinase R–like endoplasmic reticulum kinase (PERK), which mediates one arm of the UPR, restored translation of synaptic proteins, reduced neuronal loss, and prevented the onset of serious symptoms for at least 12 weeks in prion-infected mice.⁵ Unfortunately, PERK inhibition can result in pancreatic toxicity, causing the mice to experience excessive weight loss.

Moreno and her colleagues at the University of Cambridge continued to search for other ways to target the UPR. Downstream of PERK, phosphorylation of eukaryotic translation initiation factor 2α (eIF2α) acts to reduce protein synthesis; the researchers screened more than one thousand small molecule drugs and found two—trazodone hydrochloride and dibenzoylmethane—that restored protein synthesis in vitro and were neuroprotective in mice with prion disease.⁶ They were not the only ones interested in this pathway. Other research groups, including teams at Denali Therapeutics and Calico Life Sciences, developed drugs that act on a related protein, eIF2B, which is also downstream of PERK. These drugs are currently in clinical trials for the treatment of ALS and vanishing white matter disease, another neurodegenerative disorder.^7,8 

Meanwhile, Moreno returned to CSU in 2014, where she is currently an assistant professor. Her colleagues at CSU, including Popichak and Candace Mathiason, a pathobiologist and founder of the CSU Women in Science Network (WiSCI), emphasized Moreno’s strengths both as a scientist and a collaborator. “Julie promotes collaboration and inclusivity so beautifully,” said Popichak. “It’s immensely refreshing.” 

Mathiason agreed. “It’s been a pleasure working with her,” she said. “[Julie is] incredibly dedicated to her science. She has a robust curiosity and a tenacity to continue her work.”

Moreno’s current research combines elements of her graduate and post-graduate work; she explores the interaction between neuroinflammation and protein misfolding in prion disease and in aging-associated neurodegenerative diseases. According to Moreno, these two processes are closely linked: Neuroinflammation increases the likelihood of misfolding proteins, and these misshapen proteins exacerbate neuroinflammation in a vicious spiral leading to neuronal loss and dysfunction. To test potential interventions, Moreno teamed up with the Colorado-based Sachi Bioworks, a company developing RNA-targeting therapeutics. 

The team tested a cocktail of two therapeutics to disrupt the translation of two pro-inflammatory factors: nuclear factor kappa B (NF-κB) and the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome. In mice infected with prions, this therapeutic cocktail reduced neuronal loss and postponed the development of cognitive and behavioral deficits, suggesting potential applications for other neurodegenerative disorders related to protein misfolding.⁹

While Moreno plans to continue exploring pathological mechanisms and interventions in prion-diseased mice, she’s also expanding her horizons to make her work more translational. 

“One of the biggest issues when we are trying to figure out how to stop Alzheimer’s disease is that mouse studies often do not translate into humans,” said Moreno. While rodent cognition does decline with age, rodents do not naturally develop Alzheimer’s-like neuropathology.¹⁰ Canines, however, have brains that age in a remarkably similar fashion to human brains. As they age, around one third of dogs sporadically develop canine cognitive dysfunction (CCD), with similar symptoms as Alzheimer’s disease and even similar pathology, including neuroinflammation and accumulation of amyloid beta and hyperphosphorylated tau proteins.¹¹

Moreno intends to apply the lessons learned from mouse studies—what kinds of therapies are safe and effective for ameliorating neurodegeneration—to aging canines. “The mouse still has a role, those types of experiments are still super important,” she said. “But I think we have to have a middle ground to test [therapies] in an animal that translates to humans better.”

For example, in the drug repurposing study by the University of Cambridge team, the researchers found that trazodone restored eIF2α-inhibited protein synthesis. Trazodone is relatively safe—it is approved for use in humans and is commonly used to treat anxiety in dogs—so Moreno, in collaboration with CSU veterinary neurologists, is currently testing whether this medication can help pet dogs with CCD. She is excited about the possibilities of this work, not just for the translational potential to humans, but for the dogs as well. “We all love our dogs, right? For us to be able to help people and animals that are affected by this [cognitive decline] would be huge.” 

Julie is immensely kind. Everyone who works in her lab has nothing but good things to say about her. She sees them as people first and foremost, prior to seeing them as scientists. 

 —Katriana Popichak, Colorado State University

Throughout her busy research career, Moreno has always made time for mentorship. Remembering how her own journey began, Moreno has made it her mission to show students that an interest in science can lead to a weird and wonderful variety of career paths. 

“Research is essential for enabling doctors, dentists, and veterinarians to help people and animals,” she said. “They have to have people like us sitting in a lab trying to figure out the answers.” Research may offer an exciting alternative to these more traditional professional degrees that still enables students to work toward similar goals, such as alleviating suffering by improving the understanding, prevention, and treatment of illnesses.

“She really goes out of her way to make sure undergraduate students are included in research,” said Popichak. 

Moreno has also made her laboratory a welcoming space and has carefully cultivated a positive environment for students.  “Everyone who works in her lab has nothing but good things to say about her. She sees them as people first and foremost, prior to seeing them as scientists,” said Popichak.

“Julie is a fabulous person,” agreed Mathiason. “She’s incredibly dedicated to her students.”

Moreno’s support for others extends far beyond her own laboratory. She serves as the WiSCI associate director and has been instrumental in organizing the Innovating Minds lecture series, according to Mathiason. Moreno has also been a driving force behind the programs for K-12 students at the annual WiSCI symposium, organizing experiences to introduce students to a variety of STEM careers.

In a discipline that can be intensely toxic, Moreno brings positivity, inclusivity, and respect. “In a world of cranky old white men, she is the beacon for me and for many others,” said Popichak. 

Julie Moreno was nominated for this recognition through The Scientist’s Peer Profile Program submissions.

Correction: September 16, 2024: An earlier version of the story stated that Julie Moreno completed a fellowship at the University of Cambridge. The text has been updated to the correct institution, the Medical Research Council Toxicology Unit, which was affiliated with the University of Leicester at the time.