The role of autophagy in neurodegenerative diseases

Research has shed light on the cause of neurodegenerative conditions such as dementia, Parkinson’s disease and Huntington’s disease.

Discover

Forecasts suggest there is an emerging dementia and neurodegeneration ‘epidemic’, with the number of people diagnosed with dementia expected to triple to almost 150 million worldwide by 2050. The number of people diagnosed with Parkinson’s disease is also forecast to rise to more than 12 million by 2040. This ‘epidemic’ is expected to have an increasing impact on the UK and societies across the globe. In 2021, dementia and Alzheimer’s accounted for 10.4% of all deaths in England and Wales, according to ONS data, making it the second-highest cause of death, with Covid-19 the leading cause that year. Studies have found that most ageassociated neurodegenerative diseases are caused by the accumulation of toxic, intracellular, aggregate prone proteins.

The discovery of these proteins was made by many groups, including Dr Michel Goedert and Professor Maria Spillantini, in Cambridge. Currently, there is no cure for these neurodegenerative diseases, so research to understand the process behind these conditions is vital. Cambridge is at the heart of some of this research. David Rubinsztein, professor of molecular neurogenetics and interim director of the UK Dementia Research Institute at the University of Cambridge, and his team discovered that these diseasecausing proteins are removed from cells by a process called autophagy. Further research has since shown how mutations causing some neurodegenerative diseases can reduce autophagy, which leads to the accumulation of toxic proteins.

Rubinsztein’s laboratory has also shown levels of proteins that cause these neurodegenerative diseases can be reduced by activating autophagy, either with genetic strategies or using small molecule drugs. As a result, this lessened the neurodegeneration and signs of disease in animal tests. These findings have been replicated by other groups, and have led to autophagy being a focus of numerous biotech and pharma companies aiming to tackle neurodegeneration. The aim is that autophagy induction may be able to delay the onset – and slow the progression – of diseases such as Huntington’s, forms of Parkinson’s disease, and certain dementias.

Develop

The research and findings by Professor Rubinsztein and his team aim to tackle this emerging ‘epidemic’ and have led to drugdiscovery efforts, including looking into the role of repurposing drugs that already exist. The team has been working closely with Professor Roger Barker, at Cambridge University’s clinical neuroscience department, to test the effectiveness of these repurposed drugs in patients. One of the drugs that induces autophagy and clears toxic proteins associated with neurodegeneration is felodipine, a calcium channel blocker and anti-hypertensive drug.

Research suggests it can clear toxic proteins in animals. Importantly, they showed that felodipine activated autophagy in the brain, enhanced the clearance of a neurotoxic protein, and ameliorated neurodegeneration in a Parkinson’s disease mouse model at concentrations similar to those seen in humans taking the drug for hypertension.

Further research is being carried out to test if this can be applied to humans. Rubinsztein’s lab is aiming to identify additional safe and effective autophagy-enhancing drugs that work in the brain and may be suitable for neurodegenerative diseases using genetic and chemical screens. This will be complemented by studies aiming to understand how autophagy is normally regulated in cells. Furthermore, in collaboration with Alfred Goldberg’s lab at Harvard Medical School, it has been exploring the potential of stimulating degradation of neurotoxic proteins via the other key protein-degradation route used by cells: the proteasome.

The ability to interpret clinical trials with such drugs will be assisted by new scanning technologies. These are being developed to determine the micro-structural changes that happen before dementia occurs and the validation of scalable tools. In addition, Professor Sir David Klenerman, in the Dementia Research Institute in Cambridge, is developing methods to assess the aggregate levels of different neurodegenerative disease-causing proteins in the blood and cerebrospinal fluid.

These approaches will support efforts to develop treatments to prevent dementia. These therapeutic strategies and analytical approaches are among many being explored for different neurodegenerative diseases. Trials will be improved based on lessons learned from recent studies and the development of more sophisticated trial designs. In addition, the increased understanding of the underlying biologies of these conditions will support attempts to delay/prevent the onset of diseases, ameliorate progression, and/or reduce symptom severity. This research is vital given the high prevalence of these conditions and aims to slow and reduce the current forecasts of the predicted dementia and neurodegeneration ‘epidemic’

Image shows an autophagosome (a cellular structure that has engulfed material which will be degraded)
Image shows an autophagosome (a cellular structure that has engulfed material which will be degraded)
Have you got an idea which needs support?

Have you got an idea which needs support?

Have you got an idea for a potential project but don't know how to get it started? Do you think you could solve a clinical problem with a...

Find out more