Scientists say Research on Brain Proteins Involved in Parkinson’s Disease is “Shaping” Up
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Scientists from around the globe have been zeroing in on the many potential causes underlying Parkinson’s disease. Much of the modern era searching has focused on protein deposits in the brain referred to as Lewy Bodies. These non-native brain deposits were first discovered and named after the German-born neurologist Frederic Lewy in 1912. The Lewy body is known to deposit in the brainstem, and also in the cerebral cortex. The presence of Lewy bodies in the substantia nigra (black substance) deep within the brainstem region has been closely associated with the development of Parkinson’s disease, and has been felt to be one its most important hallmarks. A closer look within this important structure has revealed that there are several proteins contained inside it — including alpha-synuclein, ubiquitin, neurofilament protein, and alpha B crystalline. Occasionally, Tau protein has also been found within the Lewy body, and this has proven to be another potentially important clue; Tau protein has been closely associated with Alzheimer’s as well as other neurodegenerative conditions. Alpha-synuclein filaments and other granular material have also been observed to be directly deposited into brain cells, and these direct deposits have been referred to as Lewy neurites. Much research on the underlying causes of Parkinson’s disease has focused on alpha-synuclein misfolding, which is thought to be followed by protein aggregation, and eventual formation of a Lewy body within the brain.
In the August 14th edition of Nature, Bartels and colleagues reported important information on the shape of alpha synuclein. The authors pointed out that the shape of alpha synuclein has been described as natively “unfolded” and that it becomes a helically shaped structure when it binds to lipids (fats). A more careful analysis of alpha synuclein has revealed that its shape actually is a folded tetramer (a structure made up of four small subunits), which is not what most scientists had previously assumed. This important error in describing the native shape of alpha synuclein was thought to be due to the use of “recombinant bacterial expression protocols for in vitro studies, from overexpression, from sample heating, and/or from denaturing gels for cell culture and tissue studies.” The authors hypothesized that the order of events leading to Parkinson’s disease may thus include 1- destabilization of this helically folded tetramer, 2- misfolding of alpha-synuclein, and finally 3- formation of the Lewy body. The investigators discussed the provocative idea of stabilizing the tetramer as a way to prevent or treat Parkinson’s disease.
This recent study adds important information to our understanding of Parkinson’s disease. The findings will require replication by other groups. It will be important for scientists to observe a completely crystallized structure of alpha synuclein across many species, as well as to better understand how much of alpha-synuclein exists as a tetramer shape versus an unfolded one. Our broadening of the understanding of the shape of alpha-synuclein — both before and after it misfolds — will hopefully assist scientists and clinicians in better shaping the future of Parkinson’s disease therapeutics.
Bartels T, Choi JG, Selkoe DJ. α-Synuclein occurs physiologically as a helically folded tetramer that resists aggregation. Nature. 2011 Aug 14. doi:
10.1038/nature10324. [Epub ahead of print] PubMed PMID: 21841800.
Posted: 9/1/2011 6:57:40 AM by
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