Tuesday, 17 December 2013 11:00

Following the Link from Gaucher Disease to Parkinson’s Disease

Written by  ASCB Post Staff
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pressbook GD mergeFlies expressing mutant human glucocerebrosidase develop
Parkinsonian signs. (TOP) Flies expressing different human
mutant glucocerebrosidase variants have less TH containing
cells in their brain at 22 days (the circles specify dopaminergic
cells, expressing TH) and (BOTTOM) have locomotion deficit
as tested by their climbing ability at different days. The stars
underscore the significance of the difference between flies
expressing normal human glucocerebrosidase and flies
expressing mutant human glucocerebrosidase
(N370S or L444P).
It seems an unlikely connection, and yet there is a significant link between Gaucher disease (GD), a purely genetic disease affecting lipid storage, and Parkinson's disease, a largely untreatable progressive degenerative movement disorder of the central nervous system that is often without a clear genetic cause. Those born with two recessive GD mutations, which cause a dangerous build-up of lipids, have a higher risk of developing Parkinson's disease than those with normal GD genes. More surprising is the higher risk for Parkinson's disease among carriers of GD mutation who have no overt GD symptoms, but still produce some level of the defective enzyme called glucocerebrosidase.

Since the normal job of glucocerebrosidase is to chop up certain lipids, it might be expected that GD carriers would accumulate these lipids, but this is not the case. Instead, the problem seems to be caused by accumulation of the defective enzyme itself, leading to the activation of cellular machines that dispose of defective proteins. When these machines get too busy, they can trigger a cascade that leads to cell death.

In Parkinson's, it is the death of specific cells in the brain, dubbed dopaminergic cells, that leads to development of the disease. Mia Horowitz and Gali Maor of Tel Aviv University and colleagues hypothesized that this cell death cascade is the link to Parkinson's disease. They set out to make a laboratory model of carriers of GD mutations to test their idea using Drosophila melanogaster, the easily re-engineered fruit fly. They mutated the GD enzyme, glucocerebrosidase, in a subset of neurons in fruit flies. With defective glucocerebrosidases, these flies began losing their dopamine-generating neurons, a classic symptom of Parkinson's disease. Also, the Drosophila had reduced climbing ability, the fly equivalent of Parkinsonian hypokinesis, the characteristic movement "freeze-up."

This is the first animal model in which carriers of GD mutations have demonstrated Parkinson's-like symptoms, says Horowitz. The fly model thus lends support to the idea that GD and Parkinson's disease are related through the pathways triggered by accumulation of defective proteins, a cascade that leads to dopaminergic cell death.