Study Rationale:
Recent research has linked alpha-synuclein, a sticky protein that clumps in the brains of people with Parkinson’s disease (PD), and microtubules (cell structure supports) in Parkinson’s disease (PD). Microtubules play many important roles in brain cells, supporting the remodeling, maintenance and formation of synapses, structures through which brain cells communicate. Microtubule dysfunction leads to a loss of synapses and, as a result, negatively affects the function of brain cells. While alpha-synuclein attaches to and modulates the activity of microtubules in a healthy brain, the abnormal alpha-synuclein found in PD loses this ability. This can, in turn, induce lasting inflammation with further negative consequences for synapses and the overall brain health.
Hypothesis:
The interplay between dysfunctional microtubules and alpha-synuclein may lead to an abnormal inflammatory response, which may play a key role in PD. This interplay is likely to alter microtubule proteins, giving them a unique, recognizable appearance. We hypothesize that these specific microtubule alterations, known as post-translational modifications (PTMs), can be detected in bodily fluids, such as blood plasma and cerebrospinal fluid (CSF).
Study Design:
Microtubule function can be analyzed by measuring the PTMs of the alpha-tubulin protein, the main building block of microtubules. In this study, we will first measure microtubule PTMs in the plasma and CSF of healthy people and in those of people with Parkinson’s using our own research techniques. We will then measure the levels of alpha-synuclein and molecules that signal inflammation in the CSF and plasma samples. Lastly, we will analyze the measurements using computer methods to reveal underlying molecular interaction in the cell and possible biomarkers, i.e., signs of disease-related changes.
Impact on Diagnosis/Treatment of Parkinson’s disease:
If our hypothesis is correct, the results will have an immediate impact on the development of clinical diagnostic biomarkers and open new avenues for future original research, possibly leading to the discovery of innovative disease-modifying therapies for PD.
Next Steps for Development:
We envisage the development of user-friendly and affordable diagnostic clinical tools for blood analysis. Also, a reverse engineering approach and stem-cell models would be used to further untangle the relationship between alpha-synuclein, microtubules and the inflammatory response.