Close to understanding Parkinson’s disease
CONICET/DICYT Parkinson’s disease is a neurological disorder characterized by the presence of protein deposits mainly made up of α-synuclein (α-Syn) located in the inner part of neurons in the region of the brain called substantia nigra. These deposits, known as Lewy bodies or amyloid plaques, are abnormal accumulations that do not degrade and eventually eliminate the dopaminergic neurons, the ones in charge of producing the neurotransmitter dopamine.
For this reason, to understand how and why these plaques are formed plays a vital role in the development of an effective therapy against resulting disorders; thus enabling the attack to the nucleus of the disease itself (see box). Andres Binolfi, CONICET associate researcher at the Instituto de Investigaciones para el Descubrimiento de Fármacos de Rosario (IIDEFAR, CONICET-UNR) [Institute for Drugs Discovery of Rosario] since 2015, and a group of colleagues managed to determine the structural and functional behaviour of α-synuclein, a main component of those above mentioned deposits. The study was published in Nature and Nature Commmunications on January 26.
“Knowing the behaviour of a physiological environment is a great advance and in the future; it will be possible to apply it in the design of the drugs that combat the disease”, Binolfi states. He is one of the first authors and member of the Laboratorio Max Planck de Biología Estructural, Química y Biofísica Molecular de Rosario (MPLbioR) [Max Planck Laboratory for Structural, Chemical and Biophysics Biology of Rosario].
In order to study this aspect, the researchers used the in-cell NMR technique that allowed them to obtain accurate information about the behaviour of the molecules in live cells. “There is no other atomic resolution method capable of providing that type of information in live cells. The physical principles of other methodologies simply do not permit it”, Philipp Selenko explains. He is a researcher at the In-cell NMR Laboratory of the Leibniz-Institute for Molecular Pharmacology in Berlin, one of the pioneers in the use of this technique and coordinator of the study.
This methodology allowed the scientists to describe the proteins in physiological conditions in order to know which is the native structure and to know what situations make them aggregate, get together and begin the formation of plaques observed in Parkinson’s diseased brains. “This is the first time this type of study is conducted in the natural environment where the protein exists, in the cytoplasm of a neuronal cell. We noticed that behaves similar to what is known as a monomer and appears in a displayed way” Binolfi explains.
In the development of Parkinson’s disease, there is one factor that is hypothetically considered as a participant in the pathology: oxidative damage the α-Syn suffers from. As regards this, there is a study undertaken by Binolfi –he is the first author – and that was published in Nature Communications. The scientist discovered that inside the cell and in physiological conditions, the oxidative damage is combated by a system of the cell itself, but that would only work partially in the case of α-Syn.
“We noticed that the cell has specific machinery that repairs the damage but that in two places of one extreme of the protein – called C-terminal – is not effective and that produces the accumulation of modified species that altered cell function”, Binolfi explains.
“With these results we support more the hypothesis that suggests that oxidative stress would play a role in Parkinson’s disease development, so we described a mechanism through which the damage would accumulate in that protein”, the researcher concludes.
Not only for Parkinson
The same in-cell methodology could be used to study the behaviour of other proteins that, in a similar way as it is observed in Parkinson, are aggregated to produce other neurodegenerative diseases by plaque formation. “One example is β -amyloid peptide, which is also aggregated to form amyloid plaques in Alzheimer’s disease, out of the cell in this case; or Tau protein which forms it inside the cell”, the scientist states.
Selenko, for his part, affirms that “neurodegenerative disorders that involve pathological structural re-arrangements of protein architectures could be studied with a tool to directly look at the structures of these proteins under healthy and sick cell conditions, and this is exactly what in-cell NMR and EPR (and only they) can do.