Oligodendrocyte precursor cell transplantation into a mouse model of Amyotrophic Lateral Sclerosis
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Amyotrophic Lateral Sclerosis (ALS) is a relentless disease in which motor neurons degenerate, leading to paralysis and death. Ten percent of ALS cases are familial, and mutations in 27 different genes have been linked to the disease. The first gene in which mutations were identified was that encoding superoxide dismutase 1 (SOD1). More recently, mutations in several RNA-binding proteins have also been shown cause ALS. Many of these proteins are involved in RNA splicing, most prominently TDP-43 and FUS/TLS. These RNA binding proteins are mislocalized to the cytoplasm in motor neurons and some glial cells, where they form insoluble inclusions. Depletion of RNA-binding proteins in the nucleus leads to improper splicing of RNA. An expanded repeat in the hexanucleotide repeat GGGCCC, found in the first intron of the C9ORF72 gene, has also been linked to ALS. This repeated sequence is translated into dipeptide repeat proteins (DPR), which also form aggregates in the cytoplasm. Many experimental therapies have been tested to ameliorate symptoms in animal models of ALS. Astrocytes are the most abundant non-neuronal cells that have been shown to contribute to neurodegeneration in ALS. Astrocytic dysfunction leads to motor neuron degeneration, which may be mediated in part by downregulation of the glutamate transporter GLT1. The resulting extracellular glutamate causes excitotoxicity, which leads to motor neuron death. Other glial cells, like oligodendrocytes, have also been linked to ALS pathology. Oligodendrocytes’ main function is to myelinate axons, but a lesser-known function, that of providing metabolic support, has also been identified. Oligodendrocytes are rich in a monocarboxylate transporter, MCT1, which exports lactate out of oligodendrocytes and into axons. In the spinal cord of ALS model mice, oligodendrocytes degenerate much earlier than MNs. Oligodendrocyte precursor cells (OPCs) quickly proliferate and differentiate into oligodendrocytes, which have a reduced level of MCT1. Consequently, these new immature oligodendrocytes are thought to provide insufficient metabolic support to motor neurons. In the present study, we transplanted lineage-restricted oligodendrocyte precursor cells into the cervical spinal cord of SOD1G93A mice to assess survival of cells, denervation of muscle fibers by axons of motor neurons, and forelimb grip strength, a functional assay of muscle denervation. To date, we have not seen a significant decrease in grip strength between mice into which OPCs were transplanted and controls, although grip strength in both groups of mice increased during the first 30 days post-surgery. This experiment is ongoing and the mice will be analyzed at later post-surgical time points, including the experimental endpoint at 160 days, when survival of spinal cord motor neurons will again be assayed.
Thesis (M.A.)--Boston University