Trials to treatments: recycling in brain cells

Ongoing research suggests that problems with recycling in brain cells could contribute to Parkinson’s. We take a look at some drugs in clinical trials that aim to lend a helping hand to this recycling process.

Katherine Fletcher
Apr 1 · 6 min read

Despite decades of research, we still have an incomplete understanding of what causes Parkinson’s. But it’s thought that problems with protein build-up may be involved. In most neurodegenerative conditions there is evidence that brain cells become clogged up with old or damaged proteins, stopping them from doing their job properly. Over time these brain cells could be lost, leading to the symptoms of Parkinson’s or Alzheimer's for instance.

A recycling problem

Our bodies are made up of billions of cells. And different cells have different functions. It’s essential that these cells are kept healthy and free of waste in order for them to function properly. One way cells are kept ‘clean’ is through their very own recycling system, made up of structures called lysosomes. These are self-contained sacks of digestive enzymes that are able to break down material within the cell. The recycled components can then handily be used as building blocks to make new things.

Recycling needs to be tightly controlled by different genes and proteins in cells, we will talk more about this later. When the recycling process is not working efficiently this can lead to waste building up. This can alter the cells’ behaviour and can lead to the cells being lost.

This is like if there was a strike and our bins didn’t get collected for a while — the recycling system breaks down, and eventually, the area would get filled with rubbish and have knock-on effects to the surroundings.

In Parkinson’s, these knock-on effects include the building up of clumps of a sticky protein called alpha-synuclein — a major component of Lewy bodies, which can have toxic effects on brain cells. Research has also suggested that alpha-synuclein may cause the spread of problems from cell to cell inside the brain.

Also, there can be a build up of dysfunctional and damaged mitochondria. These are the powerhouses of our cells — essential to keeping the cells working. But when damaged mitochondria aren’t recycled, they can release toxic molecules that can overwhelm brain cells.

What causes recycling problems in Parkinson’s?

There is a lot we don’t know about why the recycling process is potentially altered in Parkinson’s. Research suggests that the process of recycling slows down as we age and therefore could contribute to the health of our brain cells.

What we do know is that there are some small changes in our genes that can make us more susceptible to developing conditions such as Parkinson's.

A couple of examples of these small genetic changes that increase our risk of developing Parkinson’s are in the GBA1 and LRRK2 genes. These genes hold the instructions to make proteins that are involved in the recycling system in our brain cells.

The GBA1 gene holds the instructions to make a protein called glucocerebrosidase (or GCase), an enzyme found in the lysosome. GCase is thought to interact with alpha-synuclein and prevent it from clumping together. So when there is a change in this gene, the GCase protein doesn’t work properly. This decreases recycling and increases the number of alpha-synuclein clumps, causing toxic effects on brain cells. Finding ways to restore or even increase GCase activity may provide a route to protecting brain cells in Parkinson’s.

The LRRK2 gene holds the instructions for the LRRK2 enzyme that controls many processes within the cell, including recycling. This gene can have small changes that cause it to produce an over-active form of the LRRK2 enzyme. This over-activity is thought to cause a problem with the recycling system, leading to unwanted proteins building up inside brain cells.

Can we encourage more recycling to help treat Parkinson’s?

Scientists have used these known genetic changes that cause a decrease in recycling to investigate treatments that could potentially overcome these problems. Although this research is focused on people who have genetic mutations in GBA1, or LRRK2-associated with Parkinson’s, this could provide vital clues relevant to all types of Parkinson’s.

Let’s see what’s happening…

Ambroxol

Ambroxol was originally developed and tested as a cough medicine but now is undergoing clinical trials as a potential treatment for Parkinson’s.

Ambroxol has been shown to increase the activity of GCase in lysosomes. This allows waste to be removed from the cell, keeping brain cells healthy and functional.

Researchers at University College London are conducting a small clinical trial in 20 people with Parkinson’s — 10 with and 10 without GBA1 mutations — to confirm the safety of ambroxol. The study will also assess the drug’s ability to get into the brain and investigate if it can lower alpha-synuclein levels.

There is also a second phase 2 trial of ambroxol underway in Canada, which will involve 75 people with Parkinson’s dementia, to see whether it can improve memory and thinking problems.

Keep an eye on our website for any updates. And you can read more about ambroxol in our previous blog on repurposed drugs.

LTI-291

Similar to ambroxol, LTI-291 also increases the activity of the enzyme GCase, thereby boosting the effectiveness of the lysosome. Clinical trials so far have shown that it is safe and well tolerated in healthy individuals. LTI-291 is now in a phase 1b trial in the Netherlands to look at how the drug acts in people with GBA associated Parkinson’s.

SAR402671 (Venglustat)

SAR402671 is slightly different. It aims to reduce the production of the proteins that the GCase enzyme breaks down rather than trying to increase the enzyme’s activity. This should have similar outcomes — to help lower the build-up of waste including alpha-synuclein.

A phase 2 clinical trial of SAR402671, is underway with one of the research sites being in London. This trial is happening in over 200 people and is focusing on people with early-stage GBA-linked Parkinson’s. The recruitment to this trial is now closed — however, you can find other opportunities near you using our regularly updated Take Part Hub.

DNL201 and DNL151

DNL201 and DNL151 are LRRK2 inhibitors that aim to stop the problems that the over-active LRRK2 enzyme has brain cells, including recycling. Both drugs are currently in phase 1 trials.

DNL201 has been shown to be safe in healthy individuals is now in a phase 1b trial in 30 people with Parkinson’s in the US.

A study investigating DNL151 in people with Parkinson’s is currently recruiting within the UK. Read the full participant information sheet and find contact details for the study team on our Take Part Hub.

These clinical trials are ongoing and offer one way to target the accumulation of waste in our cells. This could help keep cells healthier for longer and delay the progression of Parkinson’s. More work into this area is needed to see if these drugs are beneficial in the long term to people with Parkinson’s.

Parkinson’s UK

Get the latest research news, discover more about Parkinson’s and read about how others are getting involved. For information and support, visit www.parkinsons.org.uk

Katherine Fletcher

Written by

Research Communications Officer

Parkinson’s UK

Get the latest research news, discover more about Parkinson’s and read about how others are getting involved. For information and support, visit www.parkinsons.org.uk

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