Research could lead to control for damage from seizures and neurodegenerative diseases
Seizures resulting from epilepsy or brain trauma cause brain nerve cells, or neurons, to die. Although that may seem to be a straightforward process, the mechanisms causing neuronal death are complex.
Such changes result, in part, from biological factors that may have opposing activities, producing positive and negative effects.
“This is quite common in biology, that everything is a balance,” says Wilma J. Friedman, professor of cellular neurobiology in the Department of Biological Sciences at Rutgers-Newark. Friedman and her laboratory study proteins known as neurotrophins and proneurotrophins. These factors affect neuron cell functions including growth, synaptic development and survival or death.
Friedman’s work focuses on how the neurotrophic factors regulate what happens to neurons and the mechanisms or processes related to those events.
Neurons respond to factors only if the cells have specific receptors for survival or death. Normally, adult brains have few neurons with receptors for the death-inducing factor, known as p75NTR. Friedman's research has found that, during seizures such as those caused by epilepsy, the balance shifts, increasing p75NTR receptors as well as the factor that binds to them. Through this mechanism, neurons die. Her work aims to find out what might cause p75NTR to be re-expressed by seizure.
She also hopes to learn whether p75NTR has a role in the normal cell death that occurs in developing brains as connections and circuits are formed. “With injury, this natural mechanism is turned on inappropriately,” Friedman says. Identifying more about the cell death process during brain development could lead to better understanding the function of p75NTR in mature brains.
While her research has centered on neuron death after seizure, “we’re trying to see if this also relates to other conditions in which brain cells die,” she says. Her group is looking at traumatic brain injury and neurodegenerative diseases such as Alzheimer’s disease to determine if those conditions induce similar p75NTR expression.
“What we do is fundamental research,” says Friedman, “so people who are developing drugs for neurodegenerative diseases can know what to target.”
In one investigative effort, Friedman and her colleagues wanted to know how neurons in the central nervous system (brain and spinal cord) with both types of receptors respond when exposed to survival and death-promoting factors simultaneously. This frequently happens after an injury.
The researchers thought the survival pathway would prevail, as happens in the peripheral nervous system. “To our surprise,” Friedman says, “when we gave them both growth factors, the death signal won out.” The thesis work of one of her graduate students, Wenyu Song, “demonstrated the mechanism by which the death pathway predominated.” Friedman’s laboratory is now looking at how signaling pathways make that survival determination.
Following another newer direction, her group is looking at situations in which p75NTR does not cause cell death. In a recent study, they showed it inhibits cell division without killing cells during development in astrocytes, large cells located with neurons in the brain and spinal cord. Additionally, they found p75NTR in neurons of the cerebellum that also do not die. These circumstances show the factor has many functions, depending on the conditions in which it is found.
“That’s what makes it [the research] interesting,” says Friedman. “You have to find out what in those contexts makes the difference.”
After receiving a B.A. in psychobiology from Oberlin College, Wilma J. Friedman earned a Ph.D. in neurobiology from The Rockefeller University. She received the Swedish Natural Sciences Council Postdoctoral Fellowship and Wenner-Gren Foundation Fellowship while conducting post-doctoral research in molecular neurobiology at the Karolinska Institute in Stockholm, Sweden. Following her post-doctoral work, Friedman did research and taught neuroscience and cell biology at the UMDNJ-Robert Wood Johnson Medical School, then was assistant professor in the Department of Pathology and Center for Neurobiology and Behavior at Columbia University College of Physicians and Surgeons. In 2001, she came to Rutgers-Newark as assistant professor in the Department of Biological Sciences. She is now full professor of cellular neurobiology. Friedman has chaired the neuroscience section of the New York Academy of Sciences and has served on several study sections for the National Institutes of Health, including Cellular and Molecular Biology of Neurodegeneration. She also serves on editorial boards of several journals.
- Rutgers Research: Following the Trail of Cell Death in Patients with Epilepsy to Find Ways to Preserve Brain Health Rutgers news, May 2011
Selected Publications (Friedman and co-authors)
- Nerve growth factor induces cell cycle arrest of astrocytes Developmental Neurobiology, Vol. 72, No. 6 (2012)
- Expression profiling of synaptic microRNAs from the adult rat brain identifies regional differences and seizure-induced dynamic modulation Brain Research, Vol. 1436 (2012)
- Matrix metalloproteinase-7 regulates cleavage of pro-nerve growth factor and is neuroprotective following kainic acid-induced seizures Journal of Neuroscience, Vol. 32, No. 2 (2012)
- Neuron-specific effects of Interleukin-1 beta are mediated by a novel isoform of the IL-1 receptor accessory protein. Journal of Neuroscience, Vol. 31, No. 49 (2011)
- ProNGF induces PTEN via p75NTR to suppress Trk-mediated survival signaling in brain neurons,Journal of Neuroscience, Vol. 30, No. 46 (2010)
- Proneurotrophins, seizures, and neuronal apoptosis Neuroscientist, Vol. 16, No. 3 (2010)
- Ligand-independent signaling by disulfide-crosslinked dimers of the p75 neurotrophin receptor, Journal of Cell Science, Vol. 122 (2009)
- Inflammatory cytokines IL-1β and TNF-α regulate p75NTR expression in CNS neurons and astrocytes by distinct cell-type-specific signalling mechanisms ASN Neuroscience, Vol. 1, No. 2 (2009)
- A central nervous system-restricted isoform of the interleukin-1 receptor accessory protein modulates neuronal responses to interleukin-Immunity, Vol. 30, No. 6 (2009)
- Activation of the p75 neurotrophin receptor through conformational rearrangement of disulphide-linked receptor dimers ,Neuron, Vol. 62, No. 1 (2009)
- Induction of proneurotrophins and activation of p75NTR-mediated apoptosis via NGF Receptor Interacting Factor (NRIF) in hippocampal neurons after seizures,Journal of Neuroscience, Vol. 28, No. 39 (2008)
- The function of p75NTR in Glia.Trends in Neurosciences, Vol. 31, No. 2 (2008)
- Interaction of survival and death signaling in basal forebrain neurons: Roles of neurotrophins and proneurotrophins.Journal of Neuroscience, Vol. 26, No. 29 (2006)
- Interactions of interleukin-1 with neurotrophic factors in the CNS: Beneficial or Detrimental?Molecular Neurobiology, Vol. 32, No. 2 (2005)