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The Journal of Neuroscience, July 1, 1999, 19(13):5159-5172
Cellular Defects and Altered Gene Expression in PC12 Cells Stably
Expressing Mutant Huntingtin
Shi-Hua
Li,
Anna L.
Cheng,
He
Li, and
Xiao-Jiang
Li
Department of Genetics, Emory University School of Medicine,
Atlanta, Georgia 30322
Expanded polyglutamine tracts cause huntingtin and other proteins
to accumulate and aggregate in neuronal nuclei. Whether the
intranuclear aggregation or localization of a polyglutamine protein
initiates cellular pathology remains controversial. We established
stably transfected pheochromocytoma PC12 cells that express the
N-terminal fragment of huntingtin containing 20 (20Q) or 150 (150Q)
glutamine residues. The 150Q protein is predominantly present in the
nuclei, whereas the 20Q protein is distributed throughout the
cytoplasm. Electron microscopic examination confirmed that most of the
150Q protein is diffuse in the nucleus with very few microscopic
aggregates observed. Compared with parental PC12 cells and cells
expressing 20Q, cells expressing 150Q display abnormal morphology, lack
normal neurite development, die more rapidly, and are more susceptible
to apoptotic stimulation. The extent of these cellular defects in 150Q
cells is correlated with the expression level of the 150Q protein.
Differential display PCR and expression studies show that cells
expressing 150Q have altered expression of multiple genes, including
those that are important for neurite outgrowth. Our study suggests that
mutant huntingtin in the nucleus is able to induce multiple cellular defects by interfering with gene expression even in the absence of aggregation.
Key words:
huntingtin; polyglutamine; PC12 cells; nuclear
localization; neurite outgrowth; gene transcription
Copyright © 1999 Society for Neuroscience 0270-6474/99/19135159-14$05.00/0
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