Fine-tuning protein production inside brain cells to tackle Parkinson’s

In this blog, we hear from scientists Professor Rohan de Silva and Dr Roberto Simone from University College London who led this important work and explain how these discoveries may lead to important new treatments for Parkinson’s.

Why proteins matter in Parkinson’s

There are thousands of different types of proteins in our bodies. They come in lots of shapes and sizes and are responsible for growth, development and the millions of tasks that keep us healthy.

Our cells are constantly making, processing and recycling proteins to make sure they have the right combination to do their jobs. And we have complex controls built into our DNA to help our cells do this well. If these don’t work properly, we can end up with too much or too little of certain proteins and this is believed to be one of the driving factors behind many neurodegenerative conditions like Parkinson’s.

Tau is a protein that plays a role in conditions including Parkinson’s, Alzheimer’s, corticobasal degeneration and progressive supranuclear palsy.

"Tau plays a really vital role inside our brain cells. It helps to stabilise and maintain the structures that allow different materials to be transported to where they are needed," explains Professor Rohan de Silva from University College London.

"We know that too much tau is detrimental. The excess, unused tau converts into toxic species that may be responsible for damaging cells and driving the spread and progression of disease. However, despite the fact that tau has been studied for more than 3 decades, until now we did not know how neuronal cells exactly control tau protein production."

Finding the key to controlling protein production

In this work just published in the journal Nature, the international team investigated a section of genetic material that does not make tau directly but helps to regulate the production of this important protein.

This section, called antisense long non-coding RNA (lncRNA), helps to fine-tune the production of tau inside brain cells. This precision is crucial for smooth functioning of the nerve cells. Read the full research paper on the Springer Nature website.

"Excitingly, we found that the lncRNA that controls tau is not unique. Other key proteins we know to be involved in these conditions, including alpha-synuclein in Parkinson’s and beta-amyloid in Alzheimer’s, are controlled by very similar lncRNAs," explains Dr Roberto Simone, first leading and co-corresponding author of the study.

"This means we may have found the key to regulating the production of a whole range of proteins involved in brain function and the development of these devastating conditions.

"It’s early days but we hope that these exciting new insights will lead to the development of drugs that can keep tau and other proteins under control, and that these therapies could be life-changing for degenerative brain conditions that as yet, we cannot slow or stop."

A new layer of understanding

"This important research unveils a new layer of cellular fine-tuning that we have been unaware of," explained Professor Jernej Ule, whose research group at UCL and the Francis Crick Institute contributed to the study.

"It involves RNA molecules that overlap with the gene encoding tau, thus presenting exciting new opportunities for developing therapies that modulate such RNAs. It’s especially exciting to see that similar RNAs are also present at many other key proteins implicated in neurological conditions, thus opening a whole new world of opportunities."

"This is a timely study," said Professor Michela A. Denti, a co-author in the study, whose group at the University of Trento in Italy is developing RNA therapies for neurodegenerative diseases caused by tau accumulation.

"The field of RNA therapeutics is developing at an unprecedented pace. The technological advances we’re witnessing will soon allow us to deliver these molecules to the most difficult district of the body to be reached: the brain."

Targeting tau to create new treatments

This research was carried out in the lab using cells and mice to investigate how these lncRNAs regulate tau. This builds upon earlier research which has suggested tau may be involved in Parkinson’s and highlighted it as a possible target for developing new treatments.

"Genetic studies have previously shown that people who have a particular form of the tau gene, called H1, are more likely to get Parkinson’s," explains Professor de Silva.

"We know that people with the H1 form of the gene produce more tau. We also know the lncRNA we’ve identified helps to limit tau production, and that studies using post-mortem brain tissue show this lncRNA may be reduced in people with Parkinson’s," explains Dr Simone.

"So, if we can find a way to boost the levels of this lncRNA, we might be able to reduce the production of tau protein which could help to slow or stop the damage to cells inside the brain.

"That’s exactly what we are working on now. Specifically, we are developing a gene therapy to deliver this lncRNA to brain cells and we’re currently testing whether this approach can reduce tau levels in mice and other animal models.

"If it’s successful, we hope to take this approach forward to be developed as a new therapy that can one day be tested in people."

Special thanks to Professor Rohan de Silva and Dr Roberto Simone for their help with this blog.

Help drive research forward

This vital research was carried out by an international team comprised of researchers from University College London (UCL), the Francis Crick Institute, the University of Trento, Italy, and the Karolinska Institute in Stockholm, Sweden. It was part-funded by Parkinson’s UK.

Because of donations from people like you, we’ve invested £100m in groundbreaking research over the past 50 years.

We’re uncovering clues to the causes of Parkinson’s. And we’re investing in promising research to discover new treatments. We’re close. But not close enough. You can make a difference.

Will you donate now and help bring these research breakthroughs closer?