CTBR/CTSC Colloquium: Exploring the Neurobiology of Down Syndrome: From Cells to Circuits and Back Again
William Mobley. MD, PhD
Professor and Chair
Department of Neuroscience
UC San Diego
NGF Signaling and Trafficking
Trophic communication between the target and the cell body of neurons has been for a longtime an active subject of research. Indeed, neurons project axons to target areas that are often far removed from their cell body. Recent advances in molecular biology have highlighted some of the mechanisms and the nature of this phenomenon. Neurotrophic factors are a class of small soluable proteins, known to regulate the development and maintenance of neurons as well as their synaptic contacts. NGF binds and activates its high affinity receptor (TrkA), and recruits a variety of signaling molecules to form a signaling complex that in turn is internalized and subsquently trafficked retrogradely to the neuron soma. The endocytosis of this complex onto an endosomal compartment is thought to be an essential component for propagating the NGF signal from the cell terminals to cell bodies.
Our projects investigate nature of NGF‐induced endosomes carried from the synapse, at the target area, to the cell body of neurons. We use a peripheral nervous system model using isolated sciatic nerve in chambers, Campanot chambers as well as traditionalPc12 cells.
NGF Signaling and Trafficking
Alzheimer's disease (AD) is an age‐related, dementing disorder of unknown cause, is the most common cause of dementia among the elderly, account for 60 to 80% of the cases, with nearly 20 million cases predicted by 2050 in the US alone. Interestingly, Research has shown that by the age of 40, nearly all Down Syndrome patients will develop symptoms of Alzheimers Disease. We have been fortunate, through a wealth of collaborations, to study the basic mechanisms of Alzheimer and Down syndrome, two common diseases that provoke profound distress and chaos in the life of patients and their relatives. Interestingly, It is therefore clear that the understanding of the mechanisms governing the biology of the brain of subjects with a triplicated chromosome 21 will clarify many of the molecular events that arise during the development of Alzheimer disease. A key event in the progress of Alzheimer's disease is the degeneration of cholinergic neurons in the basal forebrain and the subsequent acetylcholine deficit in the hippocampus, leading to memory loss. Our recent findings, using a mouse model that mimics the triplication of the chromosome 21 in humans, emphasize the complexity of those diseases and highlight the role of intracellular basic mechanisms. Following our findings on the importance of axonal transport and nerve growth factor availability at the early stages of Down's syndrome, our goal has been to study in detail the role of individual genes within the triplicated chromosome and understand their involvement in the course of the disease
Batten’s Disease‐ Stem Cells as a potential therapy
Batten’s disease, or infantile neural ceroid lipofuscinosis (INCL), is a degenerative childhood disorder whose symptoms include severe neurodegeneration, progressive blindness and seizures. Palmitoyl‐protein thioesterase 1 (PPT1 or CLN1) is a lysosomal protein whose deficiency/mutation is genetically attributed to INCL. PPT1 removes fatty acyl side chains from cysteine residues of proteins in lysosomes. Mouse models of PPT1‐/‐ demonstrate neuronal loss in the hippocampus and cerebellum as well as accumulation of autofluorescent storage material in these areas. We are establishing parameters of hNSC transplantation in mouse models of Batten disease to see whether this may be a viable cell‐based therapy for treating the brain of subjects with lysosomal stroage disorders.
We are currently pursuing studies in the treatment of Batten disease, a degenerative childhood disorder, by using mouse models transplanted with human neural stem cells (hNSC). Recent evidence by StemCells Inc. has described the isolation and transplantation of hNSC into immuno‐deficient mice, with human cells migrating and engrafting in various areas of the brain, from the olfactory bulb to the cerebellum. These cells differentiate into both neuronal and non‐neuronal cells, depending on area of engraftment.
Biology Conference Room 926HN
dc674 (at) hunter (dot) cuny (dot) edu