The focus of the Neuroapoptosis Laboratory at the University of Pittsburgh Department of Neurological Surgery, under the direction of Robert Friedlander, MD, s the study of the basic mechanisms of apoptosis, as mediated by the caspase apoptotic family in neurologic diseases. In addition, discovering novel approaches to ameliorate the impact of cell death in a variety of neurological diseases is a central theme of the Neuroapoptosis Laboratory. The role of synaptic mitochondrial vulnerability, specifically as it relates to synaptic degeneration, has been a recent focus.
The lab is evaluating the impact of apoptotic cell death, and in particular, that mediated by the caspase cell death family on the pathogenesis of neurodegenerative diseases. Neurodegenerative diseases presently being investigated are Huntington’s Disease (HD), Alzheimers Disease (AD) and Amyotrophic Lateral Sclerosis (ALS). Given that ageing plays a role in all of these diseases, the impact of normal and pathological ageing is also being evaluated. Activation of the caspase cell death cascade appears to play an important role in a variety of neurodegenerative diseases. Researchers have demonstrated that inhibition of the Caspase-1 (also known as ICE) apoptotic gene slows the progression and delays mortality in transgenic mouse models of ALS and Huntington’s disease. Furthermore, delivering caspase inhibitors directly into the brain of these transgenic mice prolongs their survival. This was the first time that any intervention had been demonstrated efficacious in a HD model. Adding relevancy to these findings, researchers have also demonstrated that caspase-1 is activated in the brain and spinal cord of humans with HD and ALS respectively. They also have demonstrated that Minocycline demonstrates neuroprotection in a mouse model of HD.
Apoptotic cell death plays a significant role in stroke as well as traumatic brain and spinal cord injury. Researchers are evaluating the impact Caspase family activation has on apoptotic cell death in these conditions. The relation of the caspase family and free radical production is also being investigated as well as targeted caspase-mediated pharmacoprotection.
Using in vitro models, researchers are evaluating both the mechanisms involved in the activation of Caspases, as well as the post-Caspase activation pathways involved in cell death. The role of inflammatory pathways in neurodegeneration continues to be a focus of research. Researchers are also evaluating the basic mechanisms of cell death, and especially as they relate to neurologic diseases.
An additional recent focus of the Neuroapoptosis laboratory has been the demonstration that neuronal melatonin is synthesized exclusively in mitochondria. This has significantly altered the understanding of the biology of this important signaling molecule. Given that the laboratory first demonstrated that melatonin receptors are located on the mitochondrial outer membrane, this suggest melatonin is made in the mitochondrial where it is secreted and then binds to its high affinity receptor. This “automitocrine” pathways modulates mitochondrial stability and neuroprotection. We have also created a new mouse model where the rate limiting step of melatonin synthesis has been knocked out. This model has features of accelerated ageing and is an important tool in our ongoing studies.