The Neuroapoptosis Laboratory at the University of Pittsburgh Department of Neurological Surgery, under the direction of Robert Friedlander, MD, focuses on 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 emphasis.
The laboratory is evaluating the impact of apoptotic cell death, and in particular, neuronal death mediated by the caspase cascade on the pathogenesis of neurodegenerative diseases. Neurodegenerative diseases presently being investigated are Huntington’s Disease (HD), Alzheimer’s 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 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 protein slows disease 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 intervention demonstrated to be 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 by inhibiting caspases.
Apoptotic cell death plays a significant role in stroke as well as traumatic brain and spinal cord injury. Researchers are evaluating the impact of caspase activation has on apoptotic cell death in these conditions. The relationship between caspases and free radical production is also being investigated as well as targeted bhrough 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 inflammation in neurodegeneration continues to be a focus of research.
An additional recent focus of the Neuroapoptosis Laboratory has been the demonstration that neuronal melatonin is synthesized exclusively in mitochondria. This initiated a paradigm shift regarding our understanding of melatonin’s mechanisms of action. Additionally, the laboratory demonstrated that melatonin receptors are located on the mitochondrial outer membrane. Together, these new findings 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. To better understand the automitocrine pathway and its effect on neuronal function, we have generated 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
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Watch the video below from the Clear Thoughts Foundation as Dr. Friedlander talks about his research into developing new strategies for preventing neuro-degenerative diseases, such as dementia.