Dr. Cahir O'Kane
University of Cambridge

Drosophila as a model for human neurological and skin disease

A major interest of our group is neuronal membrane traffic - its role in normal cell function, and the diseases that can result when it goes wrong. We use Drosophila (fruitflies) as a model system for this work - it is a gentle and undemanding laboratory pet, with a fast generation time and many existing genetic and bioinformatic resources. In spite of the differences between flies and humans, most cellular processes and genes are conserved between us and them, and understanding the functions of disease-related genes in flies can allow us to make strong predictions about their roles in human health and disease.

One gene family of interest is implicated in two human diseases: (1) Mutations in SPG6 are responsible for a dominant form of hereditary spastic paraplegia, in which spinal cord motor axons degenerate and patients lose the use of their lower limbs. Affected families have been found in Brazil, China, Japan, and in the US (of Irish and Iraqi ancestry). (2) Mutations in ichthyin are responsible for autosomal recessive congenital ichthyosis, in which skin has a reduced barrier function. Affected families have been found in Algeria, Colombia, Syria and Turkey.

While diseases caused by mutations in either of these genes are uncommon (1 in 300 000 or less), study of this gene family can not only potentially benefit the affected families, but should shed light on mechanisms of other skin or neurological diseases. Drosophila has the advantage that it has only one homolog of SPG6/ichthyin, which we have therefore christened spichthyin. Since there is only one gene in flies, loss-of-function mutations cannot be compensated by other members of the same family. We have therefore generated flies that either completely lack or that overexpress spichthyin. A variety of genetic, molecular, microscopy and cell biological approaches have revealed that its normal role is to antagonize a well-known transmembrane receptor signaling pathway. Overexpression in neurons impairs transport of proteins along axons, and synaptic proteins appear to accumulate at axonal blockages, a striking parallel with human paraplegia. Expression of human SPG6 in Drosophila cells also causes the same effects on receptor trafficking and axons as expression of Drosophila spichthyin - showing that cellular function of the human and fly proteins is conserved.