TWITCHER--A MODEL OF A HUMAN GENETIC NEUROLOGIC DISORDER

抽搐鼠是最近发现的老鼠神经系统突变体。

The twitcher is a recently discovered neurological mutant of the mouse. The underlying genetic defect is a deficiency of galactosylceramidase. The twitcher therefore is a genetically and enzymatically authentic model of human globoid cell leukodystrophy (Krabbe disease). The present application proposes to explore this model for studies of genetic galactosylceramidase deficiency, bypassing the rarity and the ethical constraints of the human disease. The research plan contains three major goals. The first goal is to characterize the twitcher model compositionally and metabolically. Detailed compositional analysis of developing brain, peripheral nerves and kidney will be carried out with a particular emphasis on the glycolipid composition, the compostion of myelin, and on the possible accumulation of galactosylsphingosine (psychosine). The mutant will also be characterized enzymatically. The metabolic characterization will include synthesis of galactosylceramide in vivo and in vitro, both in the brain and kidney. The formation and maintenance of the myelin sheath will also be studied with radioactive precursors. The results of these basic characterization experiments will be compared with available data on human patients, since one cannot ignore potential species differences even though the disease is caused by the same enzymatic deficiency. The second major goal involves purification of the normal mouse galactosylceramidase and attempts at purifying the mutant (inactive) enzyme. The final major goal is to explore several avenues of correction of the genetic defect by enzyme supplementation. Nerve graft experiments, intracerebral tranplantation of normal tissues, and bone marrow transplantation are planned for in vivo experiments. In addition, effects of exogenous, partially purified galactosylceramidase and of co-culture with normal tissues will be examined in the organotypic cultures of the twitcher spinal cord. The scientific significance of the enzyme supplementation studies is, at present, more of fundamental developmental neurobiology, rather than of clinical applications in the near future.