Recently scientists showed that the spreading of a protein called α-synuclein is the reason of spreading of Parkinson’s (see below). This was known mechanisms in mice but was now demonstrated in diseased human tissue. This is a very important discovery as it reinforces Parkure’s α-synuclein targeting approach as a way likely to produce better drugs or even a cure. We thought we’d discuss our views on α-synuclein.
Focus on α-synuclein toxicity
Parkinson’s disease can be initiated in many ways, but the available evidence points to one factor playing a central role in the disease process, and particularly in the spreading of the disease to involve more and more of the brain. This factor is the presence of small complexes (oligomers) of the protein called α-synuclein. For this reason Parkure is focusing on finding drugs that block the toxic actions of excess α-synuclein or its mutant forms.
α-synuclein as a cause and effector in Parkinson’s
α-synuclein is a protein that is a normal component of nerve cells, with normal functions at the nerve terminal, which are still the subject of research. Α-synuclein was first associated with Parkinson’s disease as the major constituent of “Lewy bodies”, which are deposits in the brain that are found in most forms of Parkinson’s. However, α-synuclein became a serious contender as a causative agent rather than a symptom, when studies of certain families with hereditary Parkinson’s disease identified a mutation in the gene encoding α-synuclein as the cause. Α-synuclein has taken centre stage in the last two years, as evidence accumulated that it was responsible for the spread of Parkinson’s disease through the nervous system. For many years, Parkinson’s disease was viewed as a disease that was specific to a small subset of nerve cells that make and use dopamine as a neurotransmitter. This is because the most recognizable major symptoms of the disease are due to malfunction and loss of these particular neurons. All treatments have focused on this aspect of the disease. However, later on it was shown that healthy human fetal cells that had been transplanted into the brains of Parkinson’s disease patients were shown in later post mortem studies to have acquired α-synuclein deposits. It seems that the normal α-synuclein in these cells has been converted by the abnormal α-synuclein in the surrounding tissue in a prion disease-like manner. Earlier this month two important pieces of research on the matter were published (1,2). The studies showed how α-synuclein spreads in diseased human brain tissue, spreading the disease.
It is clear that it is vitally important to be able to counteract the action of α-synuclein in order to cure Parkinson’s disease. In its pathological form, α-synuclein appears to act at multiple points in the biology of the nerve cell. Therefore, Parkure’s approach – looking for drugs using a living organism, which allows for a complete cellular and tissue context – is a key way forward to find chemicals that interfere with the pathological actions of α-synuclein.
- Kovacs GG, Breydo L, Green R, Kis V, Puska G, Lőrincz P, Perju-Dumbrava L, Giera R, Pirker W, Lutz M, Lachmann I, Budka H, Uversky VN, Molnár K, László L. Intracellular processing of disease-associated α-synuclein in the human brain suggests prion-like cell-to-cell spread. Neurobiol Dis., DOI: 10.1016/j.nbd.2014.05.020, published September 2014.
- Unterberger U, Lachmann I, Voigtländer T, Pirker W, Berghoff AS, Flach K, Wagner U, Geneste A, Perret-Liaudet A, Kovacs GG. Detection of disease-associated α-synuclein in the cerebrospinal fluid: a feasibility study. Clin Neuropathol. doi: 10.5414/NP300796, published online 21 August 2014.