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Volume 17, Number 9, Issue of May 1, 1997 pp. 3052-3063
Copyright ©1997 Society for NeuroscienceHeterogeneous Topographic and Cellular Distribution of Huntingtin Expression in the Normal Human Neostriatum
Received Nov. 25, 1996; revised Feb. 12, 1997; accepted Feb. 14, 1997.
Robert J. Ferrante1, Claire-Anne Gutekunst2, Francesca Persichetti3, Sandra M. McNeil3, Neil W. Kowall1, James F. Gusella3, Marcy E. MacDonald3, M. Flint Beal4, and Steven M. Hersch2 1 Geriatric Research Education Clinical Center, Bedford VA Medical Center, Bedford, Massachusetts 01730, and Neurology Department, Boston University School of Medicine, Boston, Massachusetts 02118, 2 Department of Neurology, Emory University School of Medicine, Atlanta, Georgia 30322, 3 Molecular Neurogenetics Unit, Massachusetts General Hospital, Charlestown, Massachusetts 02129, and 4 Neurochemistry Laboratory, Neurology Service, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114
A striking heterogeneous distribution of topographic and cellular huntingtin immunoreactivity was observed within the human neostriatum using three distinct huntingtin antibodies. Patchy areas of low huntingtin immunoreactivity were present in both the caudate nucleus and putamen, surrounded by an intervening area of greater immunoreactivity. Comparison of huntingtin immunoreactivity with contiguous serial sections stained for enkephalin and calbindin D28k immunoreactivities showed that the topographic heterogeneity of huntingtin immunostaining corresponded to the patch (striosome) and matrix compartments within the striatum. Huntingtin immunoreactivity was confined primarily to neurons and neuropil within the matrix compartment, whereas little or no neuronal or neuropil huntingtin immunostaining was observed within the patch compartment. There was marked variability in the intensity of huntingtin immunolabel among medium-sized striatal neurons, whereas a majority of large striatal neurons were only faintly positive or without any immunoreactivity. Combined techniques for NADPH-diaphorase enzyme histochemistry and huntingtin immunocytochemistry, as well as double immunofluorescence for either nitric oxide synthase or calbindin D28k in comparison with huntingtin expression, revealed a striking correspondence between calbindin D28k and huntingtin immunoreactivities, with little or no colocalization between NADPH-diaphorase or nitric oxide synthase neurons and huntingtin expression. These observations suggest that the selective vulnerability of spiny striatal neurons and the matrix compartment observed in Huntington's disease is associated with higher levels of huntingtin expression, whereas the relative resistance of large and medium-sized aspiny neurons and the patch compartments to degeneration is associated with low levels of huntingtin expression.
Key words: Huntington's disease; huntingtin; neostriatum; immunofluorescence; NADPH-diaphorase; nitric oxide synthase; calbindin D28k
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