Disordered proteins and Parkinson’s disease
From building tissue to transporting molecules, proteins are the workhorses of the human body. While all proteins play a crucial role in keeping the body organised, not all proteins are organised. In fact, some are intrinsically disorganised. “Intrinsically disordered protein regions (IDRs) are segments of a protein that lack a stable, defined three-dimensional structure, existing instead as a collection of dynamic conformations,” explains Alfonso De Simone, a researcher at the University of Naples Federico II. But don’t let their disorganisation fool you. Because they can readily change shape and adopt different structures, IDRs play many important roles. However, this same flexibility also makes IDRs vulnerable to errors, namely misfolding and aggregation, which have been tied to a range of neurodegenerative diseases and even cancer. The challenge is understanding why some IDRs work while others don’t. “Even with today’s advanced electron microscopy techniques and other technologies for studying molecular structures, it remains nearly impossible to study disordered regions of proteins, especially in the cellular membrane context,” adds De Simone. But that could soon change, thanks in part to the work being done by the EU-funded BioDisOrder project.
Studying alpha-synuclein’s aggregation process – from start to finish
The project, which received support from the European Research Council, has developed several innovative tools that use a combination of nuclear magnetic resonance spectroscopy and multiscale molecular simulations. With these tools in hand, researchers were able to study the complete aggregation process of alpha-synuclein (aSyn), an IDR whose aggregation has been linked to Parkinson’s disease (PD). “By describing, with unprecedented detail, the mechanisms at the origin of Parkinson’s disease, our work opens the door to developing therapies that can target aSyn aggregation,” says De Simone, who serves as the project coordinator. Researchers further highlighted the role aSyn plays in causing the mitochondrial impairment that can lead to PD. They also showed the mechanism by which aSyn mediates the docking of synaptic vesicles on the plasma membrane surface, thus triggering the neurotransmitter’s release. “This finding clarifies that aSyn, the causative protein for Parkinson’s, plays an important role in neuronal communication under normal conditions,” notes De Simone.
Findings play a role in diagnosing and treating Parkinson’s disease
The BioDisOrder project’s findings are already having a big impact in the world of medicine. De Simone himself is currently working on a new PD diagnostic tool, while the project’s research is being used in a series of drug discovery collaborations with various groups in the EU, South Korea and United States. The hope is that these lines of research will identify potential new therapies for treating PD. All the project’s research has been published in various leading scientific journals, while its biophysical methods have been made available for use by the scientific community. “There are no limits to the characterisation of biomolecular processes,” concludes De Simone. “If you introduce a method with new analytical capability, then you can solve problems that were once thought to be impossible to characterise.”
Keywords
BioDisOrder, intrinsically disordered protein regions, Parkinson’s disease, neurological disorders, proteins, neurodegenerative diseases, cancer, electron microscopy, alpha-synuclein, medicine
