Plymouth University - Neurotropic signalling

What do we already know?

The neuronal pathology of dementia with Lewy bodies (DLB) and Parkinson’s disease (PD) have been investigated with considerable interest since the discoveries of the disorders.

However, one key pathology that remains to be further explored are the effects of alpha synuclein (α-synuclein) containing inclusions in the glial cells, and the interaction of glial cells and extracellular α-synuclein in DLB and PD.

α-Synuclein is abundantly present in our brain, however it tends to misfold into toxic agregates, particularly the oligomeric form which is implicated in synucleinopathies such as DLB. These toxic forms of the protein usually tend to aggregate in intraneuronal inclusions which are known as Lewy bodies (LBs). Glial cells include microglia which, when activated, are primarily responsible for ingesting dying cells and synapses, and the release of proinflammatory molecules.

Astrocytes are glial cells which are mainly involved in maintaining neuronal health and share many functions with microglia. We would therefore aim to test the relationship between glial cells and their specific markers in human brain samples to investigate if, as the disease progresses and α-synuclein accumulates, there will be any changes in these interactions.

We also aim to investigate the effects of different mutant forms of α-synuclein in astrocyte and microglial primary culture studies. We predict a dysregulation in the ability of the glial cells to degrade the toxic α-synuclein as disease progresses and α-synuclein aggregates within the glial cells and around neurons and expect to see differences in these effects between different mutant forms of α-synuclein.

It is important to understand the relationship between glial cells and α-synuclein for further insight into the mechanistic aspects and downstream signalling involved in the degradation of the toxic forms of this protein.

What is this project trying to find out?

1. Explore changes in glia cells in DLB/PD over the course of disease.
2. Identify the glia cell signalling pathways that are affected by alpha-synuclein.
3. Explore progression and spread of glia dysfunction into other brain regions over time in DLB/PD

How will they do this?

Investigate morphological changes of glia cells (astrocytes, microglia, and oligodendrocytes) in human brain tissue samples of people affected with DLB/PD and in non-affected individuals using a set of glia specific antibodies. This will answer the question as to whether glia recruitment and subsequent dysfunction increase with increasing amounts of alpha-synuclein. Midbrain sections from DLB patients at different stages of the disease (Braak stages) will be stained with panel of antibodies.

Assess the effect of alpha-synuclein from cellular models of dopaminergic neurons with a disease relevant expression of human alpha-synuclein. We will compare the activity of different signalling cascades and cellular processes in glia cells in presence of wildtype and mutated neurons using already established co-culture assays. We will focus our analysis on signalling pathways which are important for neuron survival and normal neuronal functioning and contribution of glia cells to these processes.

We will investigate if human alpha-synuclein accumulation, inflammation, and changes in glia cells and other disease markers might spread over time in patients with DLB and PD from the midbrain to other brain areas such as the cortex. These experiments might shade light on the progression of neurodegeneration in human patients and might support the Braak staging hypothesis.

Why is this important?

This research will further inform researchers carrying out the clinical trials so they may work towards improving the design of their trials and perhaps even developing novel therapeutic approaches.

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.