An intriguingly titled symposium queried whether there was a fatal attraction between tau and alpha-synuclein (a-syn) in Parkinson’s disease. From the witness statements given by a neuropathologist, a geneticist and a protein chemist it seems more likely to be a case of a neighbors’ interaction gone badly wrong rather than a fatal attraction.

From the neuropathological perspective, Glenda Halliday, Australia, demonstrated that Parkinson’s disease (PD) is a multi-site disease in which the timing of cell loss and protein deposition differs between sites. Age and genetic make-up impacts significantly on protein deposition in PD. As Dr Halliday told the audience, “Cellular proteins in the brain commonly deposit with age. In everyone! We all hope that it will happen as late as possible but in most of us that protein will be tau more than anything else.”

Cellular proteins in the brain commonly deposit with age. In everyone!

Protein deposition is inevitable?

The statistics that caused some incredulity and depression among audience members was that age-associated β-amyloid and tau deposition occurs in over 50% of people aged over 70 years. What may be complicating the tau – a-syn story is that deposition of β-amyloid and tau in the brain can modify the regional pattern and timing of a-syn deposition.

Age-associated β-amyloid and tau deposition occurs in over 50% of people aged over 70 years

What she also noted was that slower progression of a-syn pathology occurs with earlier clinical onset, although the pattern of protein deposition at end-stage is similar to that of later onset of disease. Older age of clinical onset is associated with a more rapid disease course.

An unfortunate series of neuropathological coincidences

From her perspective, Dr Halliday does not believe on a fatal attraction between tau and a-syn. As proteins are accumulating in the brain in all of us over time, the relationship between tau and a-syn might be simply an unfortunate series of neuropathological coincidences.

Is there a down-stream regulatory effect of a-syn on tau?

From the geneticist’s perspective, the relationship looks slightly more formal than mere coincidence. Günter Höglinger, Germany, presented evidence obtained from animal models suggesting that there could be a down-stream regulatory effect of a-synon tau.

This is evidenced from studies in which a-syn inhibited the binding of tubulin to tau. This appeared to promote tau phosphorylation and to trigger tau polymerization and may spread and seed tau inclusions. If the two proteins are part of a common pathway, transcription or epigenetic modulation of one might well influence the transcription and ultimately the deposition of the other.

Tauopathies and synucleinopathies are not distinct things and there is a huge overlap in the disease pathology

As Dr Höglinger summarized, tauopathies and synucleinopathies are not distinct things and there is a huge overlap in disease pathology, even to the extent that Parkinson’s disease or one aspect of the parkinsonian condition could be an add-on to a primary tauopathy.

Genetic evidence and animal models suggest there could be a level of functional interaction between the proteins. So, in terms of the fatal attraction analogy, there may be an interaction on a genetic level. But, just as in the movie, the ‘attraction’ is one-sided.

Protein perspective

Ronald Melki, France, compared and contrasted tau and a-syn biochemistry and molecular mechanisms.

He presented evidence which showed that a-syn and tau:

  • bind to neurons and cluster at their surfaces in a similar manner
  • have common membrane partner proteins and co-cluster
  • both compromise neuronal cell membrane integrity
  • are taken up, are transported and reach the cytosol where they amplify in a similar way.

Commonalities underlie pathology?

So, both proteins have a lot in common but can one cause structural deformation and, therefore, cellular pathology that can be blamed on the other? 

It would appear not. Importantly, a-syn and tau cannot cross-seed as they share no primary structure identity. He suggested three alternative explanations of the findings of an experiment in which cross-seeding of both tau and a-syn appeared to be demonstrated. 

Alpha-synuclein and tau cannot cross-seed as they share no primary structure identity

The ‘cross-seeding’ observation could either be due to a concentration effect – neurons exposed to high concentrations of fibrillary a-syn disrupting neuronal processing – a viscosity effect that influences protein folding and accumulation – or due to imbalanced proteostasis – a disruption of the control of protein folding and abundance within a cell. Or a mixture of all three.  In Professor Melki’s opinion, these were far likelier explanations of the apparent close association of tau and a-syn in the cell than them directly interacting with each other.

No fatal attraction

Thus, while different a-syn and tau strains may cross-talk through cellular proteostasis, no fatal attraction in terms of cross-seeding is occurring

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