Expression of mutant huntingtin in glial cells contributes to the neuropathology of Huntington's disease

Huntington's disease (HD) is characterized by the preferential loss of striatal medium spiny neurons (MSNs) in the brain. Since MSNs receive abundant glutamatergic input, their vulnerability to excitotoxicity may be influenced largely by the capacity of glial cells to remove extracellular glutamate. Although growing evidence has revealed the importance of glial cells in regulating neuronal function and survival, little is known about the role of glia in HD neuropathology. In my dissertation work, I examined glial dysfunction caused by mutant huntingtin (htt) and its contribution to neuropathology of HD. First, I found that mutant htt forms aggregates in glial nuclei in HD brains and that this aggregate formation was correlated with disease progression in HD transgenic mice. Next, I demonstrated that mutant htt decreases the expression of glutamate transporters in glial cells. As a result, expression of mutant htt reduces glutamate uptake in cultured astrocytes and brain slices from transgenic HD mice. Further, I used a neuron-glia co-culture system to show that wild type glial cells protected neurons against mutant htt-mediated neurotoxicity whereas glial cells expressing mutant htt increased neuronal vulnerability. Mutant htt in cultured astrocytes also decreased their ability to protect neurons against glutamate excitotoxicity. These findings suggest that mutant htt in glial nuclei decreases the expression of glutamate transporter, thereby reducing glutamate uptake and promoting neuronal excitotoxicity in HD.