Investigating Parkinson's disease and Dementia with Lewy bodies

Parkinson’s disease (PD) and Dementia with Lewy bodies (DLB) are neurodegenerative diseases that both see nerve cells in the brain die or malfunction. When this happens, patients can experience issues such as tremors, slowness of movement, muscle stiffness, nerve pain, memory loss, and reduced motivation. Currently there is no treatment available that can cure PD or DLB.

Researchers at the University of Plymouth, led by Professor Edgar Kramer, are seeking to understand the causes and mechanisms that lead to the nerve cell deaths, with a vision towards improving current therapies for patients.

Currently there are two projects underway at the University funded by the charity BRACE, a key funder in dementia research since 1987, that aim to uncover the answers to key questions on the functions of proteins in the brain and how they work. The projects focus on applying new knowledge to inform novel methods of treating PD and DLB, and to improve the current care practices to grant patients a better quality of life.

Project 1: Neurotrophic signalling to protect neurons in Parkinson’s disease and Dementia with Lewy bodies

The receptor Ret is made by dopaminergic nerve cells (cells that release dopamine), but dopamine neurons die in PD and DLB patients. These nerve cell deaths are linked to the build-up of the protein alpha-synuclein, which might interfere with Ret and prevents it from being expressed, therefore preventing nerve cell protection and regeneration.

Scientists have found that our brains produce small amounts of glia cell line-derived neurotrophic factor (GDNF) that may be key to triggering nerve cell survival through Ret. A University of Plymouth study showed that Ret is expressed on dopaminergic cells, and that Ret is essential to mediate how GDNF works and stimulates nerve cell survival. It has been suggested that Ret needs to be activated early in the disease by GDNF, before dopamine cells have died, in order to maximise the benefits of GDNF treatments.

Professor Kramer’s team aim to shed some light on important questions in clinical neuroscience, such as; do Parkinson’s disease and DLB patients still express Ret on dying nerve cells? Does alpha-synuclein protein build-ups reduce Ret protein levels on dopamine producing nerve cells? And how do Ret and GDNF stimulate nerve cell survival?

Clinical trials have tested the effectiveness of GDNF treatments to try and prevent degeneration of the dopaminergic neurons, however so far the results are not conclusive. More knowledge of how GDNF and Ret works is needed to optimize the benefits of GDNF therapies.

Professor Kramer’s team have developed an improved model to better understand the relationship between Ret and alpha-synuclein, tracking neurological changes over time to detect whether levels of Ret increase, decrease or maintain, and to quantify what happens in the crosstalk.

Funding awarded: £89,662

Project 2: Role of ubiquitin protein ligase Nedd4.1 and Nedd4.2 in dementia with Lewy bodies (DLB)

Like all proteins, alpha-synuclein is controlled by production and degradation. Scientists know that when alpha-synuclein fails to degrade, it leads to a toxic build-up associated with nerve cell death in the brain. However, less is known about how that degradation process occurs.

Alpha-synuclein might be flagged for degradation by two related protein enzymes, Nedd4.1 and Nedd4.2, so that a protease can remove any non-functional proteins and potentially prevent toxic alpha-synuclein clumps from forming.

Professor Kramer and his group are investigating the importance of the Nedd4 enzymes in protecting the brain from toxic alpha-synuclein. Decreased levels of the Nedd4.1 protein have been found in Parkinson’s disease patients, suggesting there was not enough of the protein to protect the nerve cells from dying.

Their research will investigate and define the role of Nedd4.1 and Nedd4.2 in dopaminergic neurons, and enable a more thorough understanding of the changes that leads to dementia and Parkinson’s disease. These experiments are vital to advance the relevant knowledge to develop a treatment against these devastating diseases, which might prevent, slow or even reverse them in the future.

Funding awarded: £66,626

<p>Edgar Kramer and his team, square</p>
<p>Professor Edgar Kramer on microscope</p>
<p>Edgar Kramer and PhD Bibire on microscope, square</p>

Institute of Translational and Stratified Medicine (ITSMed)

Translational research to develop new therapeutics, diagnostics, interventions and preventative approaches for patient and public benefit.

Our focus is on three core research themes: Cancer, Clinical Neuroscience and Infection, Immunity, Inflammation.

Find out more about ITSMed