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Abstract

We have used RNA in situ hybridization to study the regional expression of the Huntington's disease gene (HD) and its rat homologue in brain and selected nonneural tissues. The HD transcript was expressed throughout the brain in both rat and human, especially in the neurons of the dentate gyrus and pyramidal neurons of the hippocampal formation, cerebellar granule cell layer, cerebellar Purkinje cells and pontine nuclei. Other brain areas expressed lower levels of the HD transcript without pronounced regional differences. Neuronal expression predominated over glial expression in all regions. HD mRNA was also expressed in colon, liver, pancreas and testes. The regional specificity of neuropathology in HD, which is most prominent in the basal ganglia, thus cannot be accounted for by the pattern of expression of HD.

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A comprehensive set of sequence analysis programs for the VAX.

John Devereux, Paul E. Haeberli, Oliver Smithies (1984)

The University of Wisconsin Genetics Computer Group (UWGCG) has been organized to develop computational tools for the analysis and publication of biological sequence data. A group of programs that will interact with each other has been developed for the Digital Equipment Corporation VAX computer using the VMS operating system. The programs available and the conditions for transfer are described.

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Differential loss of striatal projection neurons in Huntington disease.

R L Albin, C J D'Amato, A. Reiner … (1988)

Huntington disease (HD) is characterized by the loss of striatal projection neurons, which constitute the vast majority of striatal neurons. To determine whether there is differential loss among different populations of striatal projection neurons, the integrity of the axon terminal plexuses arising from the different populations of substance P-containing and enkephalin-containing striatal projection neurons was studied in striatal target areas by immunohistochemistry. Analysis of 17 HD specimens indicated that in early and middle stages of HD, enkephalin-containing neurons projecting to the external segment of the globus pallidus were much more affected than substance P-containing neurons projecting to the internal pallidal segment. Furthermore, substance P-containing neurons projecting to the substantia nigra pars reticulata were more affected than those projecting to the substantia nigra pars compacta. At the most advanced stages of the disease, projections to all striatal target areas were depleted, with the exception of some apparent sparing of the striatal projection to the substantia nigra pars compacta. These findings may explain some of the clinical manifestations and pharmacology of HD. They also may aid in identifying the neural defect underlying HD and provide additional data with which to evaluate current models of HD pathogenesis.

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Does impairment of energy metabolism result in excitotoxic neuronal death in neurodegenerative illnesses?

F Beal (1992)

The etiology of nerve cell death in neuronal degenerative disease is unknown, but it has been hypothesized that excitotoxic mechanisms may play a role. Such mechanisms may play a role in diseases such as Huntington's disease, Parkinson's disease, amyotropic lateral sclerosis, and Alzheimer's disease. In these illnesses, the slowly evolving neuronal death is unlikely to be due to a sudden release of glutamate, such as occurs in ischemia. One possibility, however, is that a defect in mitochondrial energy metabolism could secondarily lead to slow excitotoxic neuronal death, by making neurons more vulnerable to endogenous glutamate. With reduced oxidative metabolism and partial cell membrane depolarization, voltage-dependent N-methyl-D-aspartate (NMDA) receptor ion channels would be more easily activated. In addition, several other processes involved in buffering intracellular calcium may be impaired. Recent studies in experimental animals showed that mitochondrial toxins can result in a pattern of neuronal degeneration closely resembling that seen in Huntington's disease, which can be blocked with NMDA antagonists. NMDA antagonists also block neuronal degeneration induced by 1-methyl-4-phenylpyridium, which has been implicated in experimental models of Parkinson's disease. The delayed onset of neurodegenerative illnesses could be related to the progressive impairment of mitochondrial oxidative phosphorylation, which accompanies normal aging. If defective mitochondrial energy metabolism plays a role in cell death in neurodegenerative disorders, potential therapeutic strategies would be to use excitatory amino acid antagonists or agents to bypass bioenergetic defects.

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DOI:: 10.1038/ng1193-259

PubMed ID:: 8275091

ScienceOpen disciplines: Chemistry

Keywords: Amino Acid Sequence,Animals,Base Sequence,Brain,metabolism,Cloning, Molecular,Colon,DNA,Humans,Huntington Disease,genetics,In Situ Hybridization,Liver,Male,Molecular Sequence Data,Pancreas,RNA, Messenger,Rats,Rats, Sprague-Dawley,Sequence Homology, Nucleic Acid,Testis

Widespread expression of the human and rat Huntington's disease gene in brain and nonneural tissues.

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Most cited references 12

A comprehensive set of sequence analysis programs for the VAX.

Differential loss of striatal projection neurons in Huntington disease.

Does impairment of energy metabolism result in excitotoxic neuronal death in neurodegenerative illnesses?

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