Interview of Prof Bruno Samorì, Department of Biochemistry, G Moruzzi University, Bologna, Italy

Good Morning, Prof Samorì.

The news that an important discovery about alpha-synuclein was made in an Italian laboratory is reason for national pride and has interested our readers, who would like to know something more about the researcher who made the discovery.  Tell me something about your life.

I was born in Romagna and graduated in industrial chemistry at the University of Bologna, where I started to work as a researcher.  I went repeatedly  to the US (Berkeley CA, Abuquerque NM and Eugene OR) to train as a researcher in the 1980s.  There I carried out research on DNA biochemistry and biophysics and met a few of the greatest experts in the field, such as Ignacio Tinoco and Carlos Bustamante.  In the late 1980s I contributed to the application of the atomic force microscope, which had just been invented by IBM in Zurich, in the field of biology and learned the nanotechnology offered by this instrument.  At present I dedicate my efforts to the nanotechnology-biology interface.  Nanotechnology is exploited to study biological systems; conversely, biological systems give scientists ideas on how to develop new nanotechnology.  The research team that made the discovery related to alpha-synuclein includes very young chemists, biologists and physicists (PhD students or young post-doc researchers).  We adopt a multidisciplinary approach because the most innovative nanotechnologies develop only when diverse competencies are integrated in order to achieve synergy.  

How did you get the idea of carrying out this kind of research? 

The policy of the laboratory I manage is to continue to set higher and higher hurdles to overcome.   Quoting my friend Bustamante " being a scientist means always operating at the borderline between competency and incompetency; if you always feel competent you are not carrying out your work as you should"  .   About two years ago I decided  to enter a completely new field i.e. amyloid aggregation, because the classical biochemical and biophysical techniques used up till then had not thrown much light on protein aggregation processes leading to diseases, such as Alzheimer's, Parkinson's, BSE etc. I decided therefore to attempt to apply the "single molecule" techniques to one of these proteins for the first time.  I already had experience with these techniques in the study of  DNA-protein recognition mechanisms and in the identification of the active form of angiostatin, a structured protein with antitumoral activity.

I chose alpha-synuclein because within a FIRB project co-ordinated by Prof. Rizzarelli of the University of Catania I was able to set up a co-operation with Prof. Bubacco of the Biology Institute of the University of Padua, which was able  to express the protein structures containing alpha-synuclein required for our study.

What difficulties did you have to overcome to complete the study?

The study of a new investigational method involves the demonstration of its usefulness and significance within its proposed setting.  This means that numerous verifications and accurate control studies require much more effort (both in terms of time and resources) than its actual preparation and development .

What did you actually discover?

Before we carried out our research it was believed that there was an intermediate alpha-synuclein derivative that led to the protein deposits (Lewy bodies) that are found in the brain of patients with Parkinson's disease.  Subsequently some authors suggested that alpha-synuclein might assume different forms in conformational equilibrium and that only one of them with a beta-leaflet was responsible for aggregation. 
The application of our single-molecule technique enabled us to finally "see" and assess different forms of alpha-synculein before initiation of aggregation.  This was important because all forms may be present even in healthy subjects, but at concentrations that are too low to trigger the onset of disease.  Genetic mutations in hereditary forms of Parkinson's disease and copper ions lead to an increase in beta-forms.  Thus, these findings pave the way for novel preventive measures.
 

What are the practical applications of your discovery?

The technique that we have developed can be used to verify whether individual environmental or pharmacological agents alter the conformational equilibrium of alpha-synuclein increasing beta-forms that tend to aggregate.  Nowadays Lewy bodies are considered to be garbage deposits full of old alpha-synuclein molecules that the cell is unable to eliminate and initiation of aggregation is considered to be the most dangerous phase.  Consequently, we have to be sure that any therapeutic measures intervene before aggregation begins and does not reverse the process when the molecules have been deposited in Lewy bodies.  In the past these bodies were considered a therapeutic target instead.  

Thus, our technique enables researchers to verify what  a proposed treatment actually does and enables them to discard any therapies that could be more harmful than beneficial because they release alpha-synuclein from the Lewy bodies. 

What are your plans for the future?

We intend taking advantage of the technique to assess the therapeutic potential of a series of peptides that may be able to block alpha-synuclein aggregation.   Some of these peptides have been called "beta-blockers" , because it is believed that they can block the formation of the beta structures in the deposits (they have nothing to do with the antihypertensive agents that block the beta receptors of the sympathetic nervous system)   We intend verifying whether they act before aggregation actually starts or later on.  We have also started studies designed to confirm that copper ions are an environmental risk factor for the development of Parkinson's disease.

We are also involved in research on other neurodegenerative diseases, such as  Alzheimer's disease and Bovine Spongiform Encephalopathy also called "mad cow disease".