Deficient Wnt signalling in synapse degeneration and its contribution to PD

Lead Research Organisation: University College London
Department Name: Cell and Developmental Biology

Abstract

In Parkinson's disease (PD), dopamine (DA) producing nerve cells or neurons in a brain area called substantia nigra (SN) progressively degenerate. These neurons make connections, called synapses, with neurons in another brain area, the striatum, which is essential for coordination of body movement, regulation of fine-motor movement (known as dexterity) and inhibition of involuntary movement. Thus, the loss of connections or synapses between the SN and the striatum contributes to motor deficits observed in people with PD. Several animal models of PD exhibit loss and dysfunction of synapses in the striatum, which is accompanied by defects in motor coordination in the absence or before dopamine neuron death. These findings suggest that synapse loss is an early event in PD. Although great progress has been made in the identification of some of genes involved in PD, little is known about the mechanisms that contribute to the maintenance of synapses and what triggers synapse degeneration in PD. Currently no effective cure or treatments to slow or stop disease progression are available for PD. Importantly, methods for detection of this disease at early stages are not available. Therefore, there is a great need to understand the molecular mechanisms that regulate synapse stability and what triggers their loss in PD.

These studies will provide the foundations for the development of novel therapeutic targets that protect synapses and therefore prevent or delay the onset of PD
In the last two decades, great progress has been made in understanding how synapses form during early development. However, much less is known about how nerve cells maintain their connections or synapses in the adult brain. Importantly, there is very little knowledge of the mechanisms that trigger the loss and/or dysfunction of synapses in neurodegenerative diseases. Our research group has been studying the cellular and molecular mechanisms that regulate the formation and growth of synapses in the young brain using the mouse as a model organism. Recently, we have become interested in unraveling the mechanisms that triggers synapse loss in neurodegenerative diseases.

With the aim to study synapse degeneration, we generated a transgenic mouse model that produces a secreted protein in the brain resulting in the loss of synapses in the adult striatum. These mice also exhibit defects in motor coordination similar to those observed in animal models of PD. Our studies led to the discovery of a novel function for a family of secreted proteins in synapse maintenance in the adult brain.

Our transgenic mouse model is an invaluable genetic tool for elucidating the mechanisms that lead to synapse disassembly and dysfunction in the adult and ageing brain. In this project, we plan to use these mice to identify the proteins that contribute to synapse degeneration using novel molecular techniques. We will characterise the function of these molecules in the striatum using a combination of molecular, cellular, electrophysiological and behavioural approaches. These molecules could serve as therapeutic targets aimed at protecting synapses and ameliorating the symptoms in PD. In this proposal we will address the following questions: 1) What are the molecular underpinnings of synapse degeneration? 2) How does synapse loss affect neuronal circuits within the adult striatum? 3) How is synapse vulnerability affected during aging, a major risk factor for PD?

Overall our studies will shed new light into the molecular mechanisms that maintain and protect synapses in the striatum and therefore contribute to the development of new treatments for PD. Moreover, molecules that mediate early synaptic loss could serve as biomarkers to diagnose PD at early stages.

Technical Summary

Mounting evidence suggests that synapse loss and dysfunction are early events in Parkinson's disease. Importantly, synapse vulnerability might contribute to the subsequent degeneration of dopamine neurons. However, little is known about how synapses degenerate.

Several studies support a role for deficient canonical Wnt signalling in PD. To test the contribution of this signalling pathway in neuronal and synaptic degeneration, we generated inducible transgenic mice that express the secreted Wnt antagonist Dickkopf-1 (Dkk1) in the adult striatum. These mice exhibit degeneration of cortico-striatal and dopaminergic synapses accompanied by motor defects without neuronal loss. Thus, these mice provide an ideal model to unravel the mechanisms that contribute to synapse vulnerability.

Our main objectives are:
1) What are the mechanisms that trigger synapse degeneration in the adult striatum? Through our high through put analyses we have identified key molecules that are affected during synapse degeneration in Dkk1 mice. We will examine the functional contribution using in vivo gain and loss of function experiments to test their function in synapse vulnerability, neuronal death and motor behaviour.

2) What is the impact of deficiency in Wnt signalling on synaptic transmission and plasticity in the adult striatum? Here we will use electrophysiological approaches to determine the impact of deficient Wnt signalling on striatal circuits using specific transgenic lines that label striatal neurons of the direct and indirect pathways.

3) Does deficient Wnt signalling increase synapse and cell vulnerability in ageing? Although ageing is a major risk factor in PD, little is known about how synapses change and become vulnerable during ageing. We will examine how deficiency in Wnt signalling in the striatum affects synapses in ageing animals.

Planned Impact

Clinical impact: Parkinson's disease is a devastating neurodegenerative disease affecting 1% of the population over 65 years of age, and this percentage increases with age. Parkinson's disease patients will suffer from a plethora of motor insufficiencies followed by cognitive decline. Unfortunately, patients are only diagnosed when >60% of neurons have died. Although treatment can ameliorate some of the symptoms, there is no cure or means to slow the disease progression. To develop novel and effective treatments for this debilitating disease, we need to obtain a deep understanding of the cellular and molecular mechanisms that take place during early stages of the disease. There is also a great need for identifying biomarkers that allow the early detection the disease. Work proposed in this project will address these two main issues, the identification of potential targets for therapy and early biomarkers.

Economic and societal impact: novel therapies will likely improve the standard of living of patients afflicted by PD and will alleviate the economical burden to the healthcare system and also the emotional burden to the persons around the patient. Therefore, identifying therapies that offer a prolonged and healthier lifespan will immeasurably benefit both the economic and societal health.

Research and development: our research project will provide an excellent career path for the named postdoctoral fellows and other people working in this project. The research co-investigartor Dr Soledad Galli, is aiming to establish her own research group in the near future focused on the understanding of the molecular mechanisms that lead to neuronal degeneration in the midbrain such as PD and Huntington' s disease.

Publications

10 25 50
 
Description Dementia Strategy Board at UCL
Geographic Reach Local/Municipal/Regional 
Policy Influence Type Influenced training of practitioners or researchers
 
Description ERC (European Research Council) Panel Member LS5
Geographic Reach Europe 
Policy Influence Type Influenced training of practitioners or researchers
 
Description MRC board in Neuroscience
Geographic Reach National 
Policy Influence Type Participation in a advisory committee
 
Description Project Grant
Amount £205,576 (GBP)
Funding ID ARUK-IRG2016A-7 
Organisation Alzheimer's Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 04/2016 
End 03/2019
 
Description Characterization of transgenic mice expressing a Wnt antagonist 
Organisation University of Pennsylvania
Department Department of Dermatology
Country United States 
Sector Academic/University 
PI Contribution We are characterizing transgenic mice expressing a Wnt antagonist in the adult brain
Collaborator Contribution They provided the transgenic mice
Impact We are about to submit a paper reporting the phenotype of the transgenic mice.
Start Year 2010
 
Description Collaboration with Professor Alasdair Gibb from UCL 
Organisation University College London
Country United Kingdom 
Sector Academic/University 
PI Contribution We are conducted experiments to address the impact of Wnt signalling in synaptic connectivity
Collaborator Contribution Our Collaborator Prof Gibb provided advice on the design and analyses of electrophysiological studies
Impact research publications
Start Year 2015
 
Description Collaboration with the ARUK DDI at UCL 
Organisation Alzheimer's Research UK
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution We are planning to test compounds that could activate Wnt signalling with the view to ameliorate or restore synapse degeneration.
Collaborator Contribution ARUK will provide a range of compounds to do a screen.
Impact No outcomes yet
Start Year 2017