Understanding Neurodegenerative Disease with Prion Research

 

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. 

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.

A mouse that has been dosed with infectious prions on the other hand, is not really a mode 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. 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.