Professor Edgar Kramer - Plymouth University

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

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 treatmentsfor 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.

Further Information 

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