Study might help solve the biggest mystery of Parkinson’s

The recent discoveries that α-Synuclein(α-Syn) protein, a central player in Parkinson´s disease (PD) brain destruction, could not only pass from one neuron to another but also exist outside neuronal cells has led to major rethink on the disease. In addition, it has opened as well a world of possibilities to finally understand many of the questions that have eluded scientists for decades. And in fact, a study looking at α-Syn effects out of the cell has found that it interferes with the normal functioning of the hippocampus, the brain area for memory and learning, what might finally explain the cognitive and memory problems seen in so many PD patients. The work from the Institute of Molecular Medicine at Lisbon University also shows that among the many forms of the protein, are its oligomers (aggregation of small number of α-Syn) that are toxic, something that has been the focus of much debate and might now help solve the biggest mystery of PD, the mechanism by which the affected neurons are killed. The study will be published soon  in the Journal of Neuroscience.

PD is still mostly known as an incurable, fatal, motor disease - first are the hand tremors that none of us can ever forget after Muhammad Ali. Later, as the disease spreads and the muscles become stiffer and stiffer, to walk, talk, and even show emotions (as the facial muscles no longer respond) become impossible. Even those muscles linked to involuntary actions like swallowing or digesting food are affected. The disease affects now 7-10 millions of people worldwide but its incidence is increasing as the world population age. Only in the States 60,000 patients are diagnosed every year, and this number does not reflect the undetected thousands.

But after decades of research, scientists now know that one of the major causes of the disease is linked to α-Syn - a protein apparently involved in neuronal function - which, when incapable of working properly, ends deposited in the brain provoking malfunction and eventually death of affected neuronal populations although how exactly this happens is still not understood. We also know that dopamine-producing neurons seem particularly sensitive to the abnormal forms of α-Syn, dying in large numbers in those brain areas that control movement what explains the widespread motor symptoms. In fact, dopamine acts as messenger between these "control" regions and other neurons around the body to ensure a proper regulation of the body´s movements, and as their destruction spreads, so does the disability.

Importantly, in addition to the problems in movement control, there also the less understood neuropsychiatric symptoms; dementia and also cognitive and memory problems.

With the remarkable discovery that α-Syn could exist outside of the cells, the protein's pathological effects were no longer restricted to the inside of the cell. This was the starting point for the study of Tiago Fleming Outeiro´s group and colleagues on how α-Syn could affected memory and learning. 

Understanding the memory and learning mechanism has always been one of the biggest challenges in neuroscience. Once it was clear that the number of neurons did not increase significantly with age, the only alternative to allow memories to be collected was by changes in the connections between them. Synaptic plasticity is the ability of a synapse (the connection that carries the nerve impulse between neurons) to change its strength (so the intensity of the synaptic transmission) in response to either use or disuse. In the case of new memories or learning, the connections become strengthened, whether with extra ramifications, increased numbers of receptors to capture the signal, changes in quantity of released neurotransmitters (neural messenger proteins like dopamine) or in the way cells react to them, etc.

To try to find a possible effect of α-Syn on these processes Maria Jose´ Diogenes , Raquel B. Dias, DiogoM. Rombo -the first authors of the work,- Outeiro and colleagues exposed slices of live hippocampus to different forms of α-Syn and looked for changes. What they discovered was that the abnormally aggregated protein over stimulated several receptors crucial for synaptic plasticity, creating such a high basal level of stimulation that these synapses were now unable to respond with further increases. And since new memories depend on changes in the strength of synaptic transmissions, it is easy to see how this "overload" of activation compromises memory and learning.

The good news is that the researchers also found that by blocking these overactive receptors, synaptic transmission is restored to normal, which could be a first step towards one day developing a treatment for these symptoms in the patients.

Another question that also has remained unanswered in PD is how neurons are killed. A major problem is that we still do not know which of the several existing forms of α-Syn - from isolated proteins to oligomers to the large fibrillar deposits in the brain of the patients - is/are toxic. But in these new experiments, because the protein was added externally, it was possible to test all of them individually and show that only the oligomers were toxic. "What this suggest" says Outeiro "is that we should concentrate our efforts on this form when trying to understand (and stop) neuronal cell dysfunction and death"  

This work brings exciting new clues on how the mutated extracellular (outside of the cell) α-Syn affects the brain and could cause PD,  but might also be relevant to other neurodegenerative disorders, since mutated α-Syn is found in a number of them, including Alzheimer´s disease.

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