Role of ubiquitin protein ligase Nedd4.1 and Nedd4.2 in dementia with Lewy bodies (Pilot Grant)

See glossary at bottom of page for definition of underlined words.

Summary

The protein alpha-synuclein accumulates in patients suffering from Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). The interaction of alpha-synuclein with two other proteins, Nedd4.1 and Nedd4.2 (collectively known as Nedd4), will be investigated. A mutation of human alpha-synuclein in patients leads to an increased risk of developing PD; the interaction of Nedd4 and mutated alpha-synuclein will be studied. This will increase our understanding of protein aggregation in sufferers of DLB and PD paving the way for a potential therapeutic target for the treatment of these diseases.

What do we already know?

Alpha-synuclein accumulates in patients with dementia with Lewy bodies (DLB) and Parkinson’s disease (PD). Nedd4.1 and Nedd4.2 are two proteins found to be present in neurones containing Lewy bodies. Previous work has shown the Nedd4.1 breaks down alpha-synuclein and that Nedd4.1 protects against alpha-synuclein accumulation (and subsequent toxicity) in animal models.

What is this project trying to find out?

This project has 2 main aims:

Aim 1: Assess whether Nedd4.1 and Nedd4.2 is important during development of the dopaminergic system of the brain. The need for Nedd4.1 and Nedd4.2 to maintain aging dopaminergic neurons will also be tested.

Aim 2: A mutated form of alpha-synuclein is found in families with a strong history of PD. Does Nedd4.1 and Nedd4.2 degrade this mutated alpha-synuclein in the body? A hypothesis is that deficiency of Nedd4.1 and Nedd4.2 leads to accelerated aggregation of alpha-synuclein and formation of Lewy bodies.

How will they do this?

Aim 1: Using experimental models for deficiency in Nedd4.1 and 4.2 proteins (collectively known as Nedd4), the effects of these proteins will be tested. The role of Nedd4 in the formation of Lewy bodies will be tested by comparisons of samples in the presence and absence of Nedd4.

Aim 2: Lab-based techniques will be used to analyse the amount of Nedd4 and alpha-synuclein in samples. This will lead to understanding of how these proteins interact with each other.

Why is it important?

Alpha-synuclein has been found to accumulate in Parkinson’s disease (PD) and Dementia with Lewy bodies (DLB). The regulation of Nedd4 proteins may be vitally important in the onset of symptoms of alpha-synuclein accumulation and the appearance of disease symptoms. The requirement of Nedd4 proteins in the dopaminergic system proteins has not yet been studied and might provide an insight into potential therapeutic treatments for sufferers of PD and DLB. How Nedd4 interact with alpha-synuclein may also be a vital in understanding the formation of Lewy bodies and the basis for the genetic predisposition to PD for patients who produce human mutated alpha-synuclein.

Professor Edgar Kramer and Professor Robert Fern - Neurotrophic signalling to protect neurones in Parkinson’s disease (PD) and Dementia with Lewy bodies (DLB) (PhD Studentship)

Summary

The glia cell line-derived neurotrophic factor (GDNF) and its receptor Ret is being studied to understand how they interact with alpha-synuclein. The role of alpha-synuclein in the inherent cellular processes of Parkinson’s disease (PD) and dementia with Lewy bodies (DLB) will be investigated. studied In addition, the possible attenuation of the degeneration process by GDNF/Ret signalling will be analysed. All of this should help inform the use of GDNF/Ret activation as a therapeutic treatment for PD and DLB.

What do we already know?

Glia cell line-derived neurotrophic factor (GDNF) is currently being tested in clinical trials to prevent degeneration of dopaminergic neurones in Parkinson’s disease (PD) and Dementia with Lewy bodies (DLB). Ret is a receptor for GDNF which has been found to increase the survival of neurones in the brain. This PhD studentship looks to characterise fully the levels of Ret in cells  dying in PD pateints which have accumulated alpha-synuclein.

What is this project trying to find out?

Aim 1: To assess the amount of Ret protein in PD and DLB brains during disease progression. To correlate the amount of Ret and alpha-synuclein in brain cells in correlation with alpha-synuclein load.

Aim 2: To define the cell signalling pathways and cellular processes affected by GDNF / Ret signalling in brain neurones. The cell signalling pathways which are important for neurone survival will be focussed on.

Aim 3: The progression of neurodegeneration into other brain regions will be explored over time. 

How will they do this?

Aim 1: Brain tissue from multiple brain banks around Europe (including BRACE funded Bristol Brain Bank) will be used in this study. The amounts of Ret protein in samples will be monitored at 6 different stages of PD and DLB disease progression. In addition, the levels of alpha-synuclein in samples will be measured so a correlation between Ret and alpha-synuclein can be investigated.

Aim 2: A series of laboratory techniques will be used to understand how the biological processes in the cell are affected by Ret/GDNF and alpha synuclein. This will be achieved by analysis of neurones in the presence and absence of alpha-synuclein at different stages of disease progression.

Aim 3: The presence of alpha-synuclein, Ret and other markers of PD and DLB in the brain will be monitored at different stages of disease progression. This will allow the determination of the best time point for GDNF treatment during disease progression.

Why is this important?

This project will shed light on important open questions regarding the ongoing clinical trials using GDNF in PD and DLB patients. GDNF looks like a promising treatment for the neurodegeneration caused by PD and DLB but has so far been unsuccessful. Unlocking the potential of this treatment is of vital importance for PD and DLB patients worldwide.

Glossary 

Alpha-synuclein - A protein which accumulates in cells leading to protein aggregates associated with Parkinson’s disease and dementia with Lewy bodies.
Dopaminagenic system – The set of neurones in the brain which synthesise and release the neurotransmitter domamine.
Neurotrophic Factor – A class of peptites and small proteins which support the survival, growth and differentiation of neurones.
Therapeutic treatment – Related to the treatment of a disease.

Further Information 

Please click here for more information abouth the work of Professor Edgar Kramer