Professor Linda Greensmith is the Graeme Watts Senior Research Fellow and the Head of the Graeme Watts Laboratories at UCL Queen Square Institute of Neurology in London.
She founded the Graeme Watts Lab in 1999, supported by funds left to Brain Research UK by the family of Graeme Watts, who died of motor neuron disease (MND). Graeme’s family wanted these funds to support research to improve the basic understanding of MND and to develop therapeutic strategies. No-one at the Institute was strongly focused on MND at that time and Linda Greensmith was recruited and awarded the Graeme Watts Senior Research Fellowship with the goal of setting up a lab to take forward research into this devastating disease.
The Graeme Watts Laboratories are now at the forefront of research into MND, and drug compounds that started life there have already undergone international clinical trials in MND patients. We continue to fund work in the Graeme Watts Lab using funds from the endowment established in Graeme’s name. In 2019 we awarded this grant to support a programme of work focused on a cellular mechanism called the heat shock response, which is an endogenous cytoprotective response present in all cells that normally protects cells under stress.
Motor neuron disease (MND) describes a group of diseases affecting a particular group of neurons (called motor neurons) in the brain and spinal cord that send nerves out to skeletal muscles to control their function.
Amyotrophic lateral sclerosis (ALS) is the most common form of adult MND. It is a fatal, rapidly progressing neurodegenerative disease in which motor neurons progressively die, resulting in muscle paralysis. MND therefore robs patients of their ability to walk, talk and eventually to swallow and breathe. There is no cure for these diseases and patients with ALS typically survive for only two to five years from diagnosis.
Read more: About motor neurone disease
One of the key pathological features of MND is the abnormal clumping of proteins within motor neurons. This clumping (called protein aggregation) is also a characteristic feature of most other neurodegenerative diseases, but it affects different types of neurons in different diseases. In some of the early research undertaken in the Graeme Watts Labs, Professor Greensmith’s team demonstrated that strategies that target protein aggregation in ALS may be a possible therapeutic strategy for ALS.
The team developed a drug that they showed could work in both cellular models of ALS, where neurons are grown in a dish (in vitro), and in their mouse models of ALS (in vivo). Their results showed that treatment with a new compound called Arimoclomol prevented protein aggregation in neurons and as a result improved the disease in ALS mice. More specifically, Arimoclomol was shown to act by boosting a mechanism present in all cells called the heat shock response, which normally protects cells under stress but was less effective than normal in ALS. However, Arimoclomol was not originally designed or optimised to target this protective mechanism or to act on motor neurons within the central nervous system. The Greensmith team therefore wanted to understand more about the heat shock response and how it is changed in ALS, with the overall aim of identifying compounds that might more effectively target the heat shock response in ALS or other types of MND, either alone or in combination with other promising therapies.
As part of this programme grant, Professor Greensmith and her team worked on two key projects: (1) Characterisation of the heat shock response under ALS conditions to identify the key components of this pathway and to determine which cell populations could be targeted to rescue motor neurons in ALS, and (2) Investigating the therapeutic potential of Arimoclomol in another neurodegenerative disorder called Multisystem Proteinopathy (MSP), a disease that is caused by mutations in the gene for Valosin Containing Protein (VCP) and which also results in motor neuron degeneration. As MSP is caused by mutations in a single gene (VCP), it is easier to test and monitor the effects of Arimoclomol in MSP patients as the cause of their disease is known, in contrast to ALS, where the underlying cause of disease is unknown for the vast majority of patients, resulting in great variation in disease progression.
In the first project the team found that in ALS, heat shock pathways are activated very early in the disease before symptoms appear, but initially fail to translate into effective protein-level protection until the symptomatic stages of disease. This new understanding of how the heat shock pathway changes during disease progression in ALS has allowed the team to identify various potential therapeutic targets that could enable a precision approach to treating ALS and MND.
In the second project, the team showed that treatment with Arimoclomol reduced pathology in the muscle, spinal cord and brain in their mutant VCP mouse model, as well in human neurons developed from VCP patient cells and grown in a dish, and improved muscle strength, motor neuron and cortical neuronal survival in mutant VCP mice. These results suggest that Arimoclomol may have therapeutic potential in MSP.
Motor neuron disease is a devastating, incurable condition that gradually robs people of their most basic functions. Professor Greensmith and her team have already made great strides in the quest to find effective treatments for MND, with the identification of the heat shock response as a pathway to target for the development of drugs such as Arimoclomol, which started life in the Graeme Watts Lab.
The findings from this programme grant greatly advance our understanding of molecular stress responses in motor neuron disease and support a precision approach to therapeutic targeting of heat shock response pathways in ALS. In addition, results from the work on Arimoclomol show that Arimoclomol can potentially be used to treat certain kinds of motor neuron disease, paving the way for a clinical trial of Arimoclomol in patients with Multisystem Proteinopathy.
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