Spontaneous aggregation and altered intracellular distribution of endogenous alpha-synuclein during neuronal apoptosis.
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).
Gentile
Antonietta
A
Institute of Neurobiology and Molecular Medicine, CNR, Via del Fosso di Fiorano 64-65, 00143 Rome, Italy.
Amadoro
Giuseppina
G
Corsetti
Veronica
V
Ciotti
Maria T
MT
Serafino
Annalucia
A
Calissano
Pietro
P
D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D000682:Amyloid / Q000378:metabolism; D017209:Apoptosis / Q000502:physiology*; D002449:Cell Aggregation; D002478:Cells, Cultured; D006801:Humans; D009474:Neurons / Q000378:metabolism / Q000502:physiology*; D058225:Plaque, Amyloid / Q000473:pathology; D011188:Potassium / Q000378:metabolism; D017729:Presynaptic Terminals / Q000378:metabolism; D012995:Solubility; D051844:alpha-Synuclein / Q000378:metabolism*
D000682:Amyloid; D051844:alpha-Synuclein; D011188:Potassium