London | Scientists have found a way to ‘reverse’ symptoms of neurodegenerative diseases such as Parkinson’s and Alzheimer’s – using fruit flies as test subjects. The researchers have demonstrated that genetic and pharmacological approaches can be used to lower levels of toxic metabolites in the nervous system and thereby alleviate several symptoms of neurodegeneration.
Our research is focused on better understanding of the mechanisms that contribute to onset and progression of disease symptoms in neurodegenerative disorders, said Professor Flaviano Giorgini, from the University of Leicester in UK.
These are diseases in which specific populations of nerve cells within the brain die, leading to severe problems in movement and cognitive deficits in patients, Giorgini said. The two most common neurodegenerative disorders worldwide are Alzheimer’s and Parkinson’s disease. The treatment options for these diseases are limited, and to date no cures exist, he said.
Our hope is that by improving our knowledge of how these nerve cells become sick and die in the brain, we can help devise ways to interfere with these processes, and thereby either delay disease onset or prevent disease altogether, Giorgini said. The research utilised the common laboratory fruit fly Drosophila melanogaster in order to explore the role of specific metabolites in the kynurenine pathway that cause loss of nerve cells in models of Alzheimer’s, Parkinson’s and Huntington’s diseases.
Earlier studies have shown some of these metabolites are toxic to nerve cells, and their levels are increased in these diseases. In the past, the researchers have found that they can use genetic approaches to inhibit or mute the activity of two critical enzymes in this pathway – TDO and KMO – which lowers levels of the toxic metabolites and reduces nerve cell loss in a fruit fly model of Huntington’s disease.
In the current study they have uncovered how inhibiting these two enzymes improves symptoms in flies because of increased levels of a protective kynurenine pathway metabolite known as kynurenic acid which counteracts the effects of the toxic metabolites. There is a fine balance between levels of ‘good’ and ‘bad’ metabolites that occurs in the kynurenine pathway.
In disease, it shifts towards the ‘bad’, and by inhibiting TDO or KMO, we shift it back to ‘good’, said Giorgini. For example, we find that if we inhibit either TDO or KMO in Huntington’s flies we reduce loss of neurons.
In Alzheimer’s or Parkinson’s flies we see extension of the shortened lifespan exhibited by these flies, and we also reverse the defects they have in movement, he said. We have even used a drug-like chemical to inhibit TDO and found that this also alleviates ‘symptoms’, Giorgini added.