Stimulation of synaptoneurosome glutamate release by monomeric and fibrillated α-synuclein

Sarafian, Theodore A.; Littlejohn, Kaitlyn; Yuan, Sarah; Fernandez, Charlene; Cilluffo, Marianne; Koo, Bon-Kyung; Whitelegge, Julian P.; Watson, Joseph B.

doi:10.1002/jnr.24024

Stimulation of synaptoneurosome glutamate release by monomeric and fibrillated α-synuclein

Journal Article · Mon Jan 23 23:00:00 EST 2017 · Journal of Neuroscience Research

DOI:https://doi.org/10.1002/jnr.24024· OSTI ID:1533184

Sarafian, Theodore A. ^[1]; Littlejohn, Kaitlyn ^[2]; Yuan, Sarah ^[2]; Fernandez, Charlene ^[2]; Cilluffo, Marianne ^[2]; Koo, Bon-Kyung ^[2]; Whitelegge, Julian P. ^[2]; Watson, Joseph B. ^[2]

Univ. of California, Los Angeles, CA (United States); DOE/OSTI
Univ. of California, Los Angeles, CA (United States)

The α-synuclein protein exists in vivo in a variety of covalently modified and aggregated forms associated with Parkinson's disease (PD) pathology. However, the specific proteoform structures involved with neuropathological disease mechanisms are not clearly defined. Since α-synuclein plays a role in presynaptic neurotransmitter release, an in vitro enzyme-based assay was developed to measure glutamate release from mouse forebrain synaptoneurosomes (SNs) enriched in synaptic endings. Glutamate measurements utilizing SNs from various mouse genotypes (WT, over-expressers, knock-outs) suggested a concentration dependence of α-synuclein on calcium/depolarization-dependent presynaptic glutamate release from forebrain terminals. In vitro reconstitution experiments with recombinant human α-synuclein proteoforms including monomers and aggregated forms (fibrils, oligomers) produced further evidence of this functional impact. Notably, brief exogenous applications of fibrillated forms of α-synuclein enhanced SN glutamate release but monomeric forms did not, suggesting preferential membrane penetration and toxicity by the aggregated forms. However, when applied to brain tissue sections just prior to homogenization, both monomeric and fibrillated forms stimulated glutamate release. Immuno-gold and transmission electron microscopy (TEM) detected exogenous fibrillated α-synuclein associated with numerous SN membranous structures including synaptic terminals. Western blots and immuno-gold TEM were consistent with SN internalization of α-synuclein. Additional studies revealed no evidence of gross disruption of SN membrane integrity or glutamate transporter function by exogenous α-synuclein. Finally, overall excitotoxicity, due to enhanced glutamate release in the face of either overexpressed monomeric α-synuclein or extrasynaptic exposure to fibrillated α-synuclein, should be considered as a potential neuropathological pathway during the progression of PD and other synucleinopathies.

View Accepted Manuscript (DOE)

Research Organization:: Univ. of California, Los Angeles, CA (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Biological and Environmental Research (BER); UCSD

Grant/Contract Number:: FC02-02ER63421

OSTI ID:: 1533184

Report Number(s):: JNR-2016-May-6760

Journal Information:: Journal of Neuroscience Research, Journal Name: Journal of Neuroscience Research Journal Issue: 9 Vol. 95; ISSN 0360-4012

Publisher:: WileyCopyright Statement

Country of Publication:: United States

Language:: English

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