Alpha-synuclein: The cause of Parkinson's disease
Alpha-synuclein is the key protein in Parkinson's disease: almost every patient has high levels of this protein in their brain cells. Although it occurs naturally in the body and helps with signal transmission in the brain, it becomes problematic when it undergoes pathological changes. Scientists refer to this as “misfolding”: proteins are formed when amino acids come together to build a spatial structure. If there are deviations from the blueprint, this is referred to as misfolding. In Parkinson's patients, misfolded alpha-synuclein is deposited in the nerve cells, causing damageThe protein came to the attention of scientists in 1997: Researchers first discovered that in the rare familial form of Parkinson's disease, misfolded alpha-synuclein can trigger the disease. Shortly thereafter, the next discovery was made: the characteristic Lewy bodies, which build up as deposits in the nerve cells of Parkinson's patients, consist largely of alpha-synuclein. Until then, Lewy bodies had been a mystery to researchers for many years. The link between alpha-synuclein and Parkinson's disease was thereby confirmed. Further research has since proven that misfolded alpha-synuclein proteins trigger the pathological changes associated with Parkinson's disease: they damage various nerve cells and destroy those neurons in particular that produce dopamine. This causes the typical motor symptoms of Parkinson's disease.
A chain reaction throughout the entire brain
The malicious thing is that the misfolding of proteins is, in a sense, infectious. Like a chain reaction, once misfolding occurs in one part of the brain, it spreads to adjacent areas. The different stages of Parkinson's disease can therefore be localized spatially: At the beginning, synuclein pathology—the accumulation of misfolded proteins—usually develops in the lower brain stem and then spreads to neighboring brain regions as the disease progresses. Depending on what the affected brain regions are responsible for, the symptoms of the disease then become noticeable.
It is still unclear what causes the misfolding. So why do some people develop Parkinson's disease and others do not? It is likely that age plays a role: misfolded alpha-synuclein proteins also occur in young people, but their nerve cells can still cope with them without any problems – the misfolded proteins are broken down and disposed of by the body's own waste disposal system before they can cause any damage. However, it appears that the ability of nerve cells to break down the aggregates decreases with age. This is considered one of the likely explanations. External influences are also believed to exacerbate the problem: pesticides, for example, but also various inflammations throughout life, cause more misfolding until at some point the body's own systems can no longer keep up with the breakdown. The GBA mutation is also a factor that slows down the breakdown.
Active substances in the fight against misfolding
The misfolded proteins initially move freely in the nerve cells and are probably most dangerous at this stage. Gradually, they clump together with other proteins. The Levy bodies, which contain thousands of misfolded alpha-synuclein proteins, can be thought of as nuclear waste repositories: Some nerve cells manage to store the problematic proteins there, rendering them harmless, so to speak. Lewy bodies therefore have no effect on the development of the disease – they are merely the most visible indication that a large number of misfolded proteins are present in the nerve cells.
A whole series of studies are currently testing various drugs designed to eliminate misfolded alpha-synuclein. The active ingredients being tested each use different strategies, as it is not easy to access the proteins within the cells. Scientists assume that, in the best case scenario, such a drug could prevent the progression of the disease. However, a cure is considered unlikely because the nerve cells have already suffered extensive damage. A prerequisite for these therapeutic studies is to determine the amount and type of misfolding of synuclein in the patient. To this end, so-called seed amplification assays were developed and validated at several DZNE sites (e. g. here).