The TBPH gene – do neurodegenerative diseases have a fly in the ointment?

By John Foster
Barts Cancer Institute, Queen Mary University of London, UK

This summary was highly commended by the judges for Access to Understanding 2014


A number of genes have been implicated in neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), also known as motor neurone disease, and Frontotemporal lobar degeneration (FTLD).

However, the core biological processes involved in these disorders are extremely difficult to model and this is hampering the effort to develop treatments. If we can resolve this and increase our knowledge about these disease processes it may be possible to develop new and improved treatments.

The gene TDP-43 in ALS and FTLD

The gene TDP-43 has been shown to be involved in the development of the neurodegenerative diseases ALS and FTLD in humans, however the exact way(s) in which it does this still remain unclear. This protein acts as a master regulator of RNA, a precursor to proteins, and can therefore control the expression of genes within cells. A recent study by a group led by Dr Frank Hirth from King’s College London has shed some light on this by using an interesting choice of organism: drosophila melanogaster, the common fruit fly.

A fly way to model diseases

Researchers in a wide variety of fields are looking to drosophila to model complex diseases. But why choose flies, they couldn’t be any more different biologically to us could they? In fact, fruit flies share many biological processes with us; they have a complex immune system, an intricate brain and can even develop cancer! Genes that are similar in structure and cellular function in flies and human are called homologues. They can be retained from a common ancestor by a process called evolutionary conservation. What makes the fruit fly a great model for studying disease is that it has fewer genes than humans. Where humans often have multiple genes that perform essentially the same function, a feature known as redundancy, flies often only have one gene at each stage of a signalling pathway. This means that if you alter that one gene the effect should be more obvious. Imagine calling in sick for work but no one there is able to cover for you, your work just won’t get done and others will see exactly what your role is!

Altering the function of fruit fly TBPH models neurodegenerative disease

The fruit fly homologue of the TDP-43 gene is called TBPH, and it too has been implicated in neurodegenerative disease. To investigate TBPH the researchers from King’s made fruit flies which either lacked the gene, or had increased gene expression. Interestingly, both types of fly have key symptoms of neurological disorders such as a decreased life span and motor dysfunction – this was measured by videoing the flies walking and then making recordings about the speed and gait of their movements. TBPH may therefore be considered a “goldilocks gene”, too much or too little can be biologically bad and “just the right amount” is required for normal health.

What mechanism did this study find?

To discover how loss or gain of TBPH leads to altered motility of the flies the researchers began to compare physical features of the normal fly to flies with loss of TBPH. Firstly they noted that there were no visible differences between muscle or synapse structure. This led them to dig deeper into the process of motor function. Using a series of complex experiments measuring the electrical currents generated at the gaps between neurones and muscles (neuromuscular junctions) of TBPH expressing, non-expressing or over-expressing flies, the group was able to suggest that the defects exist at the pre-synaptic stage of signal transmission. The flies have trouble transmitting neurological signals from the neurones to the muscles and this causes the physical difficulty in movement; as seen in humans with disorders driven by dysfunctional motor neurones.

Modelling the aging fly

Humans typically develop neurological diseases during old age, a fruit fly model where TBPH loss, or over-expression, was targeted only to a specific area of neurones allowed flies to age normally. It was not until flies had reached an “old age” of 40 days that they started to lose pre-synaptic function. This led ultimately to symptoms of neurodegeneration suggesting TBPH loss or over-expression has a progressive effect on neurological degeneration. Therefore, optimal TBPH levels in neurones are critical for maintaining proper motor neurone function during aging and support both the TDP-43 gene as a driver of motor neurone disorders. This study elegantly highlights the usefulness of the TBPH fruit fly model as a great way to research the underlying mechanisms behind these disorders. If more is discovered about these mechanisms then new and exciting therapeutic agents could be developed for treating neurodegenerative diseases. It is clear that when it comes to neurodegenerative disease research the flies have it!

This article describes the research published in:

Loss and gain of Drosophila TDP-43 impair synaptic efficacy and motor control leading to age-related neurodegeneration by loss-of-function phenotypes (2013) D. C. Diaper, Y. Adachi, B. Sutcliffe, D. M. Humphrey, C. J. H. Elliott, A. Stepto, Z. N. Ludlow, L. Vanden Broeck, P. Callaerts, B. Dermaut, A. Al-Chalabi, C. E. Shaw, I. M. Robinson, F. Hirth Human Molecular Genetics 22(8), 1539-1557

This article was selected for inclusion in the competition by the Motor Neurone Disease Association.