A53T Mutant Alpha-Synuclein Induces Tau-Dependent Postsynaptic Impairment Independently of Neurodegenerative Changes.

Autor:	Teravskis PJ; Department of Neuroscience.; University of Minnesota Medical School, Twin Cities, Minnesota 55455., Covelo A; Department of Neuroscience., Miller EC; Graduate Program in Neuroscience.; Department of Neuroscience., Singh B; Graduate Program in Neuroscience.; Department of Neuroscience.; University of Minnesota Medical School, Twin Cities, Minnesota 55455., Martell-Martínez HA; Department of Neuroscience., Benneyworth MA; Department of Neuroscience., Gallardo C; Department of Pharmacology Graduate Program., Oxnard BR; Department of Neuroscience., Araque A; Department of Neuroscience., Lee MK; Department of Neuroscience, liaox020@umn.edu mklee@umn.edu.; Department of Pharmacology Graduate Program.; Institute for Translational Neuroscience, University of Minnesota, Minneapolis, Minnesota 55455.; Geriatric Research, Education and Clinical Center, VA Medical Center, Minneapolis, Minnesota 55417, and., Liao D; Department of Neuroscience, liaox020@umn.edu mklee@umn.edu.; Institute for Translational Neuroscience, University of Minnesota, Minneapolis, Minnesota 55455.
Jazyk:	angličtina
Zdroj:	The Journal of neuroscience : the official journal of the Society for Neuroscience [J Neurosci] 2018 Nov 07; Vol. 38 (45), pp. 9754-9767. Date of Electronic Publication: 2018 Sep 24.
DOI:	10.1523/JNEUROSCI.0344-18.2018
Abstrakt:	Abnormalities in α-synuclein are implicated in the pathogenesis of Parkinson's disease (PD). Because α-synuclein is highly concentrated within presynaptic terminals, presynaptic dysfunction has been proposed as a potential pathogenic mechanism. Here, we report novel, tau-dependent, postsynaptic deficits caused by A53T mutant α-synuclein, which is linked to familial PD. We analyzed synaptic activity in hippocampal slices and cultured hippocampal neurons from transgenic mice of either sex expressing human WT, A53T, and A30P α-synuclein. Increased α-synuclein expression leads to decreased spontaneous synaptic vesicle release regardless of genotype. However, only those neurons expressing A53T α-synuclein exhibit postsynaptic dysfunction, including decreased miniature postsynaptic current amplitude and decreased AMPA to NMDA receptor current ratio. We also found that long-term potentiation and spatial learning were impaired by A53T α-synuclein expression. Mechanistically, postsynaptic dysfunction requires glycogen synthase kinase 3β-mediated tau phosphorylation, tau mislocalization to dendritic spines, and calcineurin-dependent AMPA receptor internalization. Previous studies reveal that human A53T α-synuclein has a high aggregation potential, which may explain the mutation's unique capacity to induce postsynaptic deficits. However, patients with sporadic PD with severe tau pathology are also more likely to have early onset cognitive decline. Our results here show a novel, functional role for tau: mediating the effects of α-synuclein on postsynaptic signaling. Therefore, the unraveled tau-mediated signaling cascade may contribute to the pathogenesis of dementia in A53T α-synuclein-linked familial PD cases, as well as some subgroups of PD cases with extensive tau pathology. SIGNIFICANCE STATEMENT Here, we report mutation-specific postsynaptic deficits that are caused by A53T mutant α-synuclein, which is linked to familial Parkinson's disease (PD). The overexpression of WT, A53T, or A30P human α-synuclein leads to decreased spontaneous synaptic vesicle release. However, only those neurons expressing A53T α-synuclein exhibit tau phosphorylation-dependent postsynaptic dysfunction, which is characterized by decreased miniature postsynaptic current amplitude and decreased AMPA to NMDA receptor current ratio. The mutation-specific postsynaptic effects caused by human A53T α-synuclein will help us better understand the neurobiological basis of this specific form of familial PD. The differential effects of exogenous human WT, A53T, A30P, and E46K α-synuclein on glutamatergic synaptic responses will help to explain the clinical heterogeneity of sporadic and familial PD. (Copyright © 2018 the authors 0270-6474/18/389755-14$15.00/0.)
Databáze:	MEDLINE
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