Spontaneous aggregation and altered intracellular distribution of endogenous α-synuclein during neuronal apoptosis

Antonietta Gentile, Giuseppina Amadoro, Veronica Corsetti, Maria T. Ciotti, AnnaLucia Serafino, Pietro Calissano

Research output: Contribution to journalArticle

Abstract

The precursor of the non-amyloid-β component of Alzheimer's disease amyloid (NACP), also known as α-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 α-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 α-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 α-synuclein intracellular redistribution and aggregation, two molecular events reminiscent of those occurring in different human neurodegenerative diseases all characterized by α-synuclein-positive inclusions. Our study indicates this in vitro neuronal system as an excellent model to dissect pathogenic mechanism(s).

Original languageEnglish
Pages (from-to)151-160
Number of pages10
JournalJournal of Alzheimer's Disease
Volume13
Issue number2
Publication statusPublished - 2008

Keywords

  • α-synuclein
  • Aggregation
  • Apoptosis
  • CGNs

ASJC Scopus subject areas

  • Neuropsychology and Physiological Psychology

Fingerprint Dive into the research topics of 'Spontaneous aggregation and altered intracellular distribution of endogenous α-synuclein during neuronal apoptosis'. Together they form a unique fingerprint.

  • Cite this