Twenty five years of the "psychosine hypothesis": a personal perspective of its history and present status

Abstract

Twenty five years ago in 1972, a hypothesis was introduced to explain the pathogenetic mechanism underlying the unusual cellular and biochemical characteristics of globoid cell leukodystrophy (Krabbe disease). It postulated that galactosylsphingosine (psychosine), which 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, the 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 twitcher mice, an equivalent murine mutant. Meanwhile this "psychosine hypothesis" has been extended to Gaucher disease and then to a more general hypothesis encompassing all sphingolipidoses that the "lyso-derivatives" of the primary sphingolipid substrates of the defective enzymes in respective disorders play a key role in their pathogenesis. Some of these extensions not only remain speculative without conclusive factual evidence but may eventually turn out to be an overstretching. This article attempts, from my personal perspective, at tracing historical development of the "psychosine hypothesis" and examining its current status and possible future directions.