Molecular mechanisms of neuronal cell death
Neurons die as a normal physiological process during development and aging, or as a pathological process in chronic neurodegenerative diseases and acute insults to the brain like TBI and stroke. Apoptosis, a type of programmed cell death, underlies neuronal death during development and contributes to the degeneration of specific populations of neurons in a variety of neurodegenerative disorders. Recent studies have indicated that other forms of programmed cell death, i.e. autophagy, may contribute to neuronal death in chronic disease and after acute insults to the brain. Understanding the molecular mechanisms that control the death of neurons is the first step to designing new drugs to slow or prevent neuronal cell loss in chronic and acute neurological disease.
Dr. Heidenreich’s laboratory uses 2 model systems to study neuronal cell death. The in vitro model utilizes cultured neurons from newborn rat cerebellum. These cultures consist of 95 % granule neurons (the most abundant neuron type in mammals), 3% Purkinje neurons, and a very small percentage of glial cells. Granule neurons thrive in the presence of serum and the presence of depolarizing extracellular potassium. When this trophic support is removed, the granule neurons die by a classic intrinsic apoptotic cascade. Purkinje neurons also die when trophic support is removed, but they die by different mechanism that involves enhanced autophagy. Thus, the cerebellar cultures allow for the investigation of factors that regulate both intrinsic apoptosis and autophagic cell death. The second model system utilized by the lab is an in vivo lateral fluid percussion model of experimental traumatic brain injury (TBI) in rats. This model mimics many of the pathological features of human TBI and allows for the search of factors that may be useful in preventing the secondary phase of brain injury that follows TBI.
Dr. Heidenreich’s laboratory has identified a number of protein kinases that trigger or prevent neuronal apoptosis in response to neuronal insults and neurotrophic factors, respectively. Ongoing research examines how these key proapoptotic and antiapoptotic protein kinases are regulated and identifies the cytoplasmic effectors and transcription factors downstream of these protein kinases. Other aspects of her research focus on the regulation of critical mitochondrial proteins activated during intrinsic apoptosis and the role of the endoplasmic reticulum (ER) in mediating neuronal death. More recent studies focus on the regulation of autophagy in neurons and its role in neuronal cell death. Using the knowledge gained from studying death signaling pathways in vitro, the laboratory hopes to find ways of preventing brain injury following TBI.