The precursor of the non-
amyloid-beta component of
Alzheimer's disease amyloid (NACP), also known as
alpha-synuclein, is a presynaptic terminal molecule that accumulates in the
senile plaques of
Alzheimer's disease. Aberrant accumulation of this
protein into insoluble aggregates has also been implicated in the pathogenesis of many other
neurodegenerative diseases, collectively referred to as
synucleinopathies. However, the precise pathogenetic mechanism that leads to aggregate formation and the consequent cellular damage remains elusive. Analyzing differentiated primary cultures of cerebellar granule neurons undergoing apoptosis due to K+ reduction from 25 mM to 5.0 mM, a neuronal model widely used to study event linking apoptosis and neurodegeneration [1], we assessed that endogenous monomeric
alpha-synuclein decreases and spontaneously aggregates into
detergent-insoluble high molecular species. Apoptosis is also correlated with a marked redistribution/accumulation of this
protein from terminal neurites to perikaria, with formation of compact inclusion bodies in juxta-nuclear area. In addition, secretion of monomeric
alpha-synuclein decreases in response to apoptotic stimulus, while part of it aggregates into fibrillar structures and becomes detectable by immunogold-electron microscope analysis. The data presented in this study demonstrate that an apoptotic event caused by a "physiological" trigger, such as neuronal membrane repolarization of cultured cerebellar granule neurons, induces
alpha-synuclein intracellular redistribution and aggregation, two molecular events reminiscent of those occurring in different human
neurodegenerative diseases all characterized by
alpha-synuclein-positive inclusions. Our study indicates this in vitro neuronal system as an excellent model to dissect pathogenic mechanism(s).