Kaufmann, Timothy J., Harrison, Paul Michael, Richardson, Magnus J. E., Pinheiro, Teresa J. T. and Wall, Mark J. (2016) Intracellular soluble α-synuclein oligomers reduce pyramidal cell excitability. The Journal of Physiology, 594 (10). 2751-2772 . doi:10.1113/JP271968 ISSN 0022-3751.

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Abstract

The presynaptic protein α-synuclein (αSyn) aggregates during Parkinson's disease (PD) to form large proteinaceous amyloid plaques, the spread of which throughout the brain clinically defines the severity of the disease. During early stages of aggregation, αSyn forms soluble annular oligomers that show greater toxicity than much larger fibrils. These oligomers produce toxicity via a number of possible mechanisms, including the production of pore-forming complexes that permeabilize membranes. In the present study, two well-defined species of soluble αSyn oligomers were produced by different protocols: by polymerization of monomer and by sonication of fibrils. The two oligomeric species produced were morphologically similar, with both having an annular structure and consisting of approximately the same number of monomer subunits, although they differed in their secondary structure. Oligomeric and monomeric αSyn were injected directly into the soma of pyramidal neurons in mouse neocortical brain slices during whole-cell patch clamp recording. Using a combined experimental and modelling approach, neuronal parameters were extracted to measure, for the first time in the neocortex, specific changes in neuronal electrophysiology. Both species of oligomer had similar effects: (i) a significant reduction in input resistance and the membrane time constant and (ii) an increase in the current required to trigger an action potential with a resultant reduction in the firing rate. Differences in oligomer secondary structure appeared to produce only subtle differences in the activity of the oligomers. Monomeric αSyn had no effect on neuronal parameters, even at high concentrations. The oligomer-induced fall in neuronal excitability has the potential to impact both network activity and cognitive processing.

Item Type:	Journal Article
Subjects:	Q Science > QP Physiology R Medicine > RC Internal medicine
Divisions:	Faculty of Science, Engineering and Medicine > Science > Life Sciences (2010- ) Faculty of Science, Engineering and Medicine > Research Centres > Warwick Systems Biology Centre
Library of Congress Subject Headings (LCSH):	Alpha-synuclein, Parkinson's disease, Oligomers, Amyloid, Monomers, Sonication
Journal or Publication Title:	The Journal of Physiology
Publisher:	Blackwell
ISSN:	0022-3751
Official Date:	12 May 2016
Dates:	Date Event 12 May 2016 Published 24 March 2016 Available 17 February 2016 Accepted 30 November 2015 Submitted
Volume:	594
Number:	10
Page Range:	2751-2772
DOI:	10.1113/JP271968
Status:	Peer Reviewed
Publication Status:	Published
Access rights to Published version:	Open Access (Creative Commons)
Date of first compliant deposit:	12 May 2016
Date of first compliant Open Access:	12 May 2016
Funder:	Biotechnology and Biological Sciences Research Council (Great Britain) (BBSRC)

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