Clinical, pathological and biochemical phenotype of globoid cell leukodystrophy (Krabbe disease) has several unique characteristics that are sometimes contrary to the conventional concept of genetic lysosomal disease. It was demonstrated early that galactosylceramide has unusual capacity to elicit a globoid cell-like reaction when implanted into the brain. Then, thirty years ago a hypothesis was introduced to explain the pathogenetic mechanism underlying the rapid and complete loss of myelin and myelinating cells. It postulated that galactosylsphingosine (psychosine), which is highly cytotoxic and also cannot be degraded due to the underlying genetic defect, is responsible for the very rapid loss of the oligodendrocytes and the consequent paradoxical analytical finding-lack of accumulation of the primary substrate, galactosylceramide, in patients’ brain. It took nearly ten years before the actual accumulation of psychosine was demonstrated in human Krabbe patients and also in the brain of mouse and dog models of the disease. During the intervening years, the psychosine hypothesis has been generally accepted as a critical pathogenetic mechanism in classical infantile globoid cell leukodystrophy. However, a more recent experimental mouse model due to genetic defect in saposin A, an in vivo galactosylceramidase activator protein, introduced new elements in our understanding of the disease process. Not only has it established the second gene, genetic defect of which can cause globoid cell leukodystrophy but it has indicated potential decoupling of the two previously postulated pathogenetic mechanisms, galactosylceramide for the globoid cell reaction and psychosine for loss of myelinating cells. Pathogenetic significance of participation of the major histocompatibility complexes and other immune mechanisms, inflammatory processes as suggested by activation of many cytokines, and possible interactions with sex hormones remain to be further explored.
(Communicated by Tamio YAMAKAWA, M. J. A., Jan. 14, 2003)
A recent study with single molecule measurements has reported that myosin II, a molecular motor, generates stochastic and multiple steps during the hydrolysis of a single ATP molecule. In order to elucidate the mechanism for the motion of myosin, we traced the movements of individual molecules by simulating the Brownian movements along the potentials created by the interaction between a myosin molecule and an actin filament. We demonstrated that Brownian movement was biased to one direction as observed for myosins by either spatially tilting or temporally fluctuating the height of the potential. We incorporated the biased Brownian movement into an ATP hydrolysis reaction scheme and studied the effects of the load on the movement. The results could successfully explain the movements and mechanical properties of myosin. Thus, it was demonstrated that the movement of myosin is thermally driven and the random motion is biased by the energy released from the ATP hydrolysis.
(Communicated by Fumio OOSAWA, M. J. A., Jan. 14, 2003)
The complete genomic DNA sequence of the thermophilic archaeon Thermoplasma volcanium is visually represented by assembling micro-squares in four color-types. The number of bases in this sequence (1,584,804) is larger than what was reported earlier (1,584,799 in Kawashima, T., Yamamoto, Y., Aramaki, H., Nunoshiba, T., Kawamoto, T. et al., 1999, Proc. Japan Acad. 75B, 213-218) by 5. These five bases (A at position 320,375, C at 342,507, T at 1,182,809, A at 1,365,060, and C at 1,376,292 in the new version) are missing from the previous version, mainly, not because of erroneous sequence reading, but due to physical deletion of corresponding base-pairs upon replication of the cloned DNA fragments in E. coli cells.
(Communicated by Masanori OTSUKA, M. J. A., Jan. 14, 2003)
Recent genetic studies of Drosophila melanogaster and subsequent biochemical analysis in mammalian cells revealed that products of tuberous sclerosis genes, TSC1 and TSC2, regulate insulin signaling via suppression of p70 ribosomal S6 subunit-kinase (S6K) activity. In this study, using transplantation in the nude mouse, we found that the growth of a renal tumor cell line from Tsc2 knockout mouse was suppressed by the treatment of rapamycin, an inhibitor of mTOR (mammalian target of rapamycin) which is an upstream activator of S6K. The robust in vivo effect of rapamycin suggests that it can be used for chemotherapy of tuberous sclerosis-associated hamartomas and tumors. Other yet undiscovered chemicals selectively downregulate mTOR-S6K pathway may provide new therapeutic drugs for tuberous sclerosis.
(Communicated by Takashi SUGIMURA, M. J. A., Jan. 14, 2003)