Exogenous α-synuclein hinders synaptic communication in cultured cortical primary rat neurons

• Published in: PloS one 2018-03, Vol.13 (3), p.e0193763
• Main Authors: Hassink, G C, Raiss, C C, Segers-Nolten, I M J, van Wezel, R J A, Subramaniam, V, le Feber, J, Claessens, M M A E
• Format: Article
• Language: English
• Subjects: Action Potentials - drug effects; Action Potentials - physiology; alpha-Synuclein - administration & dosage; alpha-Synuclein - metabolism; alpha-Synuclein - toxicity; Alzheimer's disease; Amyloid; Animals; Apoptosis; Axons; Biology and Life Sciences; Brain; Cell Survival - drug effects; Cell Survival - physiology; Cells, Cultured; Cerebral Cortex - drug effects; Cerebral Cortex - metabolism; Cerebral Cortex - pathology; Computer and Information Sciences; Cortex; Extracellular Space - drug effects; Extracellular Space - metabolism; Firing rate; Humans; Intracellular Space - drug effects; Intracellular Space - metabolism; Lewy bodies; Medicine; Medicine and Health Sciences; Movement disorders; Nanotechnology; Neurochemistry; Neurodegenerative diseases; Neurons; Neurons - drug effects; Neurons - metabolism; Neurons - pathology; Parkinson's disease; Physical Sciences; Physiology; Protein Aggregation, Pathological - pathology; Proteins; Rats, Wistar; Recombinant Proteins - administration & dosage; Recombinant Proteins - metabolism; Recombinant Proteins - toxicity; Research and Analysis Methods; Synapses - drug effects; Synapses - metabolism; Synaptic transmission; Synaptic Transmission - drug effects; Synaptic Transmission - physiology; Synuclein; Toxicity
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0193763

Amyloid aggregates of the protein α-synuclein (αS) called Lewy Bodies (LB) and Lewy Neurites (LN) are the pathological hallmark of Parkinson's disease (PD) and other synucleinopathies. We have previously shown that high extracellular αS concentrations can be toxic to cells and that neurons take up αS. Here we aimed to get more insight into the toxicity mechanism associated with high extracellular αS concentrations (50-100 μM). High extracellular αS concentrations resulted in a reduction of the firing rate of the neuronal network by disrupting synaptic transmission, while the neuronal ability to fire action potentials was still intact. Furthermore, many cells developed αS deposits larger than 500 nm within five days, but otherwise appeared healthy. Synaptic dysfunction clearly occurred before the establishment of large intracellular deposits and neuronal death, suggesting that an excessive extracellular αS concentration caused synaptic failure and which later possibly contributed to neuronal death.