TY - JOUR
T1 - Huntingtin immunoreactivity in the rat neostriatum
T2 - Differential accumulation in projection and interneurons
AU - Kosinski, Christoph M.
AU - Cha, Jang Ho
AU - Young, Anne B.
AU - Persichetti, Francesca
AU - MacDonald, Marcy
AU - Gusella, James F.
AU - Penney, John B.
AU - Standaert, David G.
N1 - Funding Information:
This study was supported by Grant DFG Ko 1696/1-1 to C.M.K. and by USPHS Grants NS31579, NS32765, and NS16367, the Glendorn Foundation, the Hereditary Disease Foundation, and the Foundation for the Care and Cure of Huntington’s disease. D.G.S. is a recipient of a Cotzias Fellowship from the American Parkinson’s Disease Association. The authors thank Dr. Ted Dawson of Johns Hopkins University for providing the nNOS antibody.
PY - 1997/4
Y1 - 1997/4
N2 - Huntington's disease is caused by a mutation of the gene encoding the protein huntingtin. Features of the human disease, characterized by selective loss of neurons from the neostriatum, can be replicated in rodents by administration of excitotoxins. In both affected individuals and the rodent model, there is massive loss of striatal projection neurons with selective sparing of interneurons. Furthermore, in the human disease the earliest evidence of striatal injury is found in striosomal regions of the striatum. The mRNA encoding huntingtin is known to be expressed by neurons throughout the brain, a distribution which does not account for the selective patterns of neuronal death which are observed. Using fluorescence immunocytochemistry and confocal microscopy with an antibody to huntingtin, we have observed that in rats a subset of striatal projection neurons contains dense accumulations of huntingtin immunoreactivity (HT-ir), while most neurons in the striatum contain much smaller amounts. The intensely stained neurons are concentrated within the striatal striosomes, as defined by calbindin-D(28K) staining. In the matrix regions, relatively few neurons contain dense accumulations of HT- ir, and these cells always lack perikaryal staining for calbindin-D(28K). Striatal interneurons, identified by the presence of immunoreactivity for choline acetyltransferase, parvalbumin, calretinin, or neuronal nitric oxide synthase, exhibit little or no HT-ir. The paucity of HT-ir in striatal interneurons, as well as the prominence of staining in a subset of striosomal neurons, mirrors the selective vulnerability of these different types of cells in early stages of human Huntington's disease and in rodent excitotoxic models of the disorder. Our observations suggest that mechanisms which modulate the accumulation of huntingtin may play a central role in the neuronal degeneration of Huntington's disease.
AB - Huntington's disease is caused by a mutation of the gene encoding the protein huntingtin. Features of the human disease, characterized by selective loss of neurons from the neostriatum, can be replicated in rodents by administration of excitotoxins. In both affected individuals and the rodent model, there is massive loss of striatal projection neurons with selective sparing of interneurons. Furthermore, in the human disease the earliest evidence of striatal injury is found in striosomal regions of the striatum. The mRNA encoding huntingtin is known to be expressed by neurons throughout the brain, a distribution which does not account for the selective patterns of neuronal death which are observed. Using fluorescence immunocytochemistry and confocal microscopy with an antibody to huntingtin, we have observed that in rats a subset of striatal projection neurons contains dense accumulations of huntingtin immunoreactivity (HT-ir), while most neurons in the striatum contain much smaller amounts. The intensely stained neurons are concentrated within the striatal striosomes, as defined by calbindin-D(28K) staining. In the matrix regions, relatively few neurons contain dense accumulations of HT- ir, and these cells always lack perikaryal staining for calbindin-D(28K). Striatal interneurons, identified by the presence of immunoreactivity for choline acetyltransferase, parvalbumin, calretinin, or neuronal nitric oxide synthase, exhibit little or no HT-ir. The paucity of HT-ir in striatal interneurons, as well as the prominence of staining in a subset of striosomal neurons, mirrors the selective vulnerability of these different types of cells in early stages of human Huntington's disease and in rodent excitotoxic models of the disorder. Our observations suggest that mechanisms which modulate the accumulation of huntingtin may play a central role in the neuronal degeneration of Huntington's disease.
UR - http://www.scopus.com/inward/record.url?scp=0031127812&partnerID=8YFLogxK
U2 - 10.1006/exnr.1997.6441
DO - 10.1006/exnr.1997.6441
M3 - Article
SN - 0014-4886
VL - 144
SP - 239
EP - 247
JO - Experimental Neurology
JF - Experimental Neurology
IS - 2
ER -