The way protein misfolding and aggregation has been studied in the field of Parkinson disease (PD) has undergone some major changes in the past 20 years. After the initial discovery of α-synuclein (αSyn) aggregates as the main component of the Lewy body, the pathologic hallmark of PD,1 the involvement of small, soluble αSyn aggregates as the putative culprit of neurotoxic effects quickly became one of the major research directions for understanding the mechanism of neurodegeneration in PD. The mechanistic studies have been challenging, however, mainly because of the complex folding behavior of αSyn. The challenges have been 2-fold. Although in vivo and cell culture models struggled with recapitulating amyloid aggregation and Lewy body formation that would mimic the neurodegeneration and protein deposits observed in patients, the in vitro studies based on recombinantly expressed protein faced the opposite problem. Although synthetic protein readily forms amyloid fibrils akin to Lewy bodies in the test tube, the exact structure and biological activity of these aggregates have been polymorphic, meaning that they highly depend on the exact in vitro conditions used for preparation. Various forms and shapes with equally diverse methods of action have emerged in the literature, but reproducibility between laboratories has been an issue, mainly owing to the specific aggregation protocols used to synthesize these species. This lack of reproducibility made it difficult to relate specific forms to those that might develop in the context of a patient’s brain.
Bartels T. Conformation-Specific Detection of α-Synuclein: The Search for a Biomarker in Parkinson Disease. JAMA Neurol. 2017;74(2):146–147. doi:10.1001/jamaneurol.2016.4813
Customize your JAMA Network experience by selecting one or more topics from the list below.
Create a personal account or sign in to: