Publication Summaries

On this page, we provide accessible summaries of PD-MitoQUANT publications. We will add to this as the project team publishes more results.

 

The differential solvent exposure of N-terminal residues provides ‘fingerprints’ of alpha-synuclein fibrillar polymorphs

Landureau M, Redeker V, Bellande T, Eyquem S, Melki R, Journal of Biological Chemistry (2021), doi: https://doi.org/10.1016/j.jbc.2021.100737.

Summary:

What is alpha-synuclein and why is it important in Parkinson’s disease?

Alpha-synuclein is a highly flexible protein that adopts multiple shapes. Prof. Ronald Melki has illustrated the dynamic properties of this protein in a cartoon made by France Parkinson and available on YouTube. Among the many shapes this protein adopts, there are forms that can interact with molecules of similar shape to form stacks that are harmful to neurons (nerve cells in the brain), in particular the neurons that synthesise dopamine. Dopamine is a chemical that transmits nerve impulses across the connections (synapses) between neurons.

These stacks of alpha-synuclein are normally removed but the clearance system is not 100% efficient and its efficiency decreases with time. Problems with the clearance system happen as we age or in people with neurodegenerative diseases, like Parkinson’s. The result is that the alpha-synuclein stacks remain and accumulate over time, leading to neuronal stress through synaptic and mitochondrial dysfunction, and ultimately to neuronal death.

There is evidence that alpha-synuclein aggregates spread from affected neurons to healthy neurons. This contamination process contributes to disease progression. Stopping this process should slow disease progression, so understanding the effects of alpha-synuclein on the brain is an area of interest for drug development for neurodegenerative diseases.

What did this study find?

We have demonstrated recently that different forms of alpha-synuclein aggregate into stacks that bind differentially to neurons, spread differentially in the brain of animal models and yield Parkinson’s characteristic Lewy bodies or inclusions in oligodendrocytes (a type of cell that supports neurons) that are the hallmark of multiple system atrophy, another pathology associated with alpha-synuclein (synucleinopathy). In this study, we identified the surfaces of distinct alpha-synuclein stacks as they define binding to neurons and interaction with cellular proteins or organelles, in particular the mitochondria.

So what do the study results mean?

One part of alpha-synuclein distinguishes one pathological stack from another, while another part characterises all pathogenic alpha-synuclein stacks. Finally, we singled out parts that are not exposed at all at the surfaces of alpha-synuclein pathogenic aggregates.

What is next?

The differential recognition of different alpha-synuclein stacks has early diagnostic, as well as therapeutic, potential. We will be validating our findings in brain tissues donated by patients to brain bio-banks. We aim to develop specific binders for distinct alpha-synuclein pathogenic aggregates. We also aim to identify the mitochondrial proteins that interact with the alpha-synuclein regions that we have identified in this paper. The latter will be done within the PD-MitoQUANT project.

 

AMPK preferentially depresses retrograde transport of axonal mitochondria during localised nutrient deprivation.

Orla WattersNiamh M. C. ConnollyHans-Georg KönigHeiko Düssmann and Jochen H. M. Prehn  2020.  doi: https://doi.org/10.1523/JNEUROSCI.2067-19.2020

Summary:

What are mitochondria and why are they important for people with neurological diseases?

The axon is a long, cable-like part of a nerve cell that helps carry information from our brain to other nerve cells and to our muscles throughout our bodies. Mitochondria act like a digestive system for the cell, taking in nutrients and breaking them down into energy. This energy is used as fuel to move them along the axon. It’s not just a one-way system though – these cells and mitochondria are constantly communicating and responding to the differing needs of each individual cell. This means that mitochondria can travel throughout the cell redirecting their energy to where it’s most needed, which is vital for healthy brain function.

There is increasing evidence that impaired mitochondrial function could be associated with many neurological diseases including stroke, amyotrophic lateral sclerosis (ALS), Alzheimer’s and Parkinson’s, but a detailed understanding of the cause and effect of this impairment is lacking.

What did this study find?

This study shows that when energy levels are critically low in a region of the axon, mitochondria can build up at the site of this energy stress. As energy is required for the movement of mitochondria, it is unsurprising that we found that when cells are under stress and running low on energy, mitochondrial movement slows down. We show that this is a result of a special protein, called AMP-activated protein kinase or AMPK becoming active. By blocking this protein, we were able to reverse the effect, increasing mitochondrial movement back to its normal levels. Our most interesting finding is that AMPK activity has a bigger effect on slowing down the movement of mitochondria away from the site of energy stress than those moving towards this region. This means that there are more mitochondria at the site of energy stress, where they work to produce more energy to try to restore the proper functioning of this region of the cell.

So, what do the study results mean?

This study shows that mitochondrial transport is altered in response to local energy stress in nerve cells. We don’t know how important this will be yet, but this research is exciting as energy stress, mitochondrial impairment and ultimately cell death play a role in the development of neurological diseases.

What’s next?

We are now continuing this research to study whether changes in mitochondrial transport are a piece of the puzzle in how impaired mitochondrial function contributes to neurological diseases as part of the PD-MitoQUANT project.