14 May Simon Bullock publishes paper pointing to cellular mechanism behind devastating neurodegenerative diseases
Lister Fellow Dr Simon Bullock has recently published a new research paper in Science Advances, entitled “C9orf72-derived arginine-containing dipeptide repeats associate with axonal transport machinery and impede microtubule-based motility.”
The study explores the disease mechanism of frontotemporal dementia (FTD) and motor neuron disease (also known as amyotrophic lateral sclerosis (ALS)). These neurodegenerative diseases can be devastating for the patients and their families and are currently incurable. The research findings may lead to new therapeutic targets and treatments.
FTD and ALS most commonly result from a mutation in the C9orf72 gene. Researchers know that cells with the C9orf72 mutation produce a number of abnormal proteins, which are highly repetitive in their sequences. But it is unclear how these so-called ‘dipeptide repeat proteins’ (DPRs) cause neurons in the spinal cord and brain to degenerate.
In this study, Simon’s lab worked with colleagues from several other institutes, including Philip Van Damme’s group at the Vlaams Instituut voor Biotechnologie in Belgium. Their paper outlines evidence that the DPRs impair the function of cellular transport machinery needed for the neuron’s survival. The DPRs bind to microtubules – long polymers within cells that act as tracks for motor proteins and their cargoes. This binding obstructs motor movement and impedes delivery of essential organelles and macromolecules.
The finding raises the possibility that boosting transport or blocking the ability of the DPRs to bind the tracks could be a new way of attempting to treat ALS and FTD.
The study used a remarkable range of techniques – from watching single molecules moving along microtubules on a glass slide to analysing transport in patient stem cell-derived neurons. “This is a great example of what can be achieved when scientists from different disciplines – clinicians, biochemists and geneticists – unite to tackle a challenging problem,” says Simon.
The DPRs bind to the microtubule tracks through a ‘tubulin tail’ that extends from their surface. A striking feature of these tails is that they are extensively modified by enzymes that add or remove various chemical groups. Simon’s team is now investigating how these modifications influence binding to the DPRs. The make-up of tubulin tails varies across different parts of the nervous system so this research could help explain why the C9orf72 mutation only affects certain types of neurons.
Simon explains that this project, and other studies of neurological disease in his group, are direct extensions of his Lister-funded work.
“Other funding bodies might have considered my proposal to shift away from our traditional models and into neuronal systems too risky, especially given our lack of a track record in neurobiology. But thankfully, Lister backed our vision.``
Simon is Group Leader at the MRC Laboratory of Molecular Biology in Cambridge. He was a recipient of a Lister Institute Research Prize in 2008. You can find out more about him and his research on his lab’s webpage.
We are delighted to have been able to support Dr Bullock’s earlier work. The Lister looks forward to hearing more about his future research.