Medium spiny neuron develop & markers

Medium spiny neuron develop & markers - 2nd...

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2nd Neuroscience Ireland Conference 323 Medium spiny neurons for transplantation in Huntington’s disease Claire M. Kelly* 1 , Stephen B. Dunnett* and Anne E. Rosser*† *Brain Repair Group, School of Biosciences, Museum Avenue, Cardiff University, Cardiff CF10 3AX, Wales, U.K., and Departments of Neurology and Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, Wales, U.K. Abstract Cell-replacement therapy for Huntington’s disease is one of very few therapies that has reported positive out- comes in clinical trials. However, for cell transplantation to be made more readily available, logistical, stand- ardization and ethical issues associated with the current methodology need to be resolved. To achieve these goals, it is imperative that an alternative cell source be identified. One of the key requirements of the cells is that they are capable of acquiring an MSN (medium spiny neuron) morphology, express MSN markers such as DARPP-32 (dopamine- and cAMP-regulated phosphoprotein of 32 kDa), and function in vivo in a manner that replicates those that have been lost to the disease. Developmental biology has progressed in recent years to provide a vast array of information with regard to the key signalling events involved in the proliferation, specification and differentiation of striatal-specific neurons. In the present paper, we review the rationale for cell-replacement therapy in Huntington’s disease, discuss some potential donor sources and consider the value of developmental markers in the identification of cells with the potential to develop an MSN phenotype. Introduction HD (Huntington’s disease) is a triplet repeat disorder char- acterized by an expansion of the CAG polyglutamine repeat unit of the huntingtin protein. It is an autosomal dominant inherited neurodegenerative disease that affects approx. 4–10 in 10000 in the Caucasian community. The disease usually manifests in the fourth and fifth decades of life and leads to a relentlessly progressive condition with death most commonly occurring within 20–30 years. The HD brain is characterized by loss of the MSNs (medium spiny neurons) of the striatum, enlargement of the ventricles and a corresponding shrinkage of the overlying cortex (Figure 1). Unlike other neurodegenerative disorders, such as Parkinson’s disease, where several options are available, albeit mainly for the early-to-moderate-stage patient, there is little in the way of disease-modifying treatment available for patients with HD. Cell-replacement therapy acts by replacing the cells that have been lost due to trauma or disease. In the case of HD, this would involve replacing the earliest and most extensive cell loss in the disease, the MSNs of the striatum. These GABAergic (GABA is γ -aminobutyric acid) cells are the most populous neuronal cell type of the striatum (90–95% in rats and over 85% in humans), along with several small pop- ulations of interneurons [3]. MSNs are characterized by their Key words: cell-replacement therapy, Huntington’s disease, medium spiny neuron, transplantation.
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