| Abstract
| - Parkinson's disease (PD) is one of many neurodegenerative diseases that are characterized byamyloid fibril formation. α-Synuclein is a primary component of the fibrillar neuronal inclusions, knownas Lewy bodies, that are diagnostic of PD. In addition, the α-synuclein gene is linked to familial PD.Fibril formation by α-synuclein proceeds via discrete β-sheet-rich oligomers, or protofibrils, that areconsumed as fibrils grow. Both FPD mutations accelerate formation of protofibrils, suggesting that theseintermediates, rather than the fibril product, trigger neuronal loss. In idiopathic PD, other factors may beresponsible for accelerating protofibril formation by wild-type α-synuclein. One possible factor could bemolecular crowding in the neuronal cytoplasm. We demonstrate here that crowding using inert polymerssignificantly reduced the lag time for protofibril formation and the conversion of the protofibril to thefibril, but did not affect the morphology of either species. Physiologically realistic changes in the degreeof in vitro crowding have significant kinetic consequences. Thus, nonspecific changes in the totalcytoplasmic protein concentration, induced by cell volume changes and/or altered protein degradation,could promote formation of and stabilize the α-synuclein protofibril.
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