Abnormalities in -synuclein are implicated in the pathogenesis of Parkinson’s disease (PD). Because -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 -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 -synuclein. Increased -synuclein expression leads to decreased spontaneous synaptic vesicle release regardless of genotype. However, only those neurons expressing A53T -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 -synuclein expression. Mechanistically, postsynaptic dysfunction requires glycogen synthase kinase 3-mediated tau phosphorylation, tau mislocalization to dendritic spines, and calcineurin-dependent AMPA receptor internalization. Previous studies reveal that human A53T -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 -synuclein on postsynaptic signaling. Therefore, the unraveled tau-mediated signaling cascade may contribute to the pathogenesis of dementia in A53T -synuclein-linked familial PD cases, as well as some subgroups of PD cases with extensive tau pathology.
|Original language||English (US)|
|Number of pages||14|
|Journal||Journal of Neuroscience|
|State||Published - Nov 7 2018|
Bibliographical noteFunding Information:
This work was supported by the National Institutes of Health [Grants R21-NS084007-01, R21NS096437-01, R01-NS NS086074, R01-092093, R01 NS108686-01 (to M.K.L., D.L., and A.A.), National Institute on Drug Abuse Training Grant T32 DA07234, Predoctoral Training Grant P32-GM008471 (to E.C.M.); and National Institute on Aging-funded predoctoral fellowship to T32-AG029796 to C.G.]; the Michael J. Fox Foundation; a UMN–Mayo partnershipgrantandagrantfromMinnesotaHigherEducation(D.L.);theSusanandDavidPlimptonFund(M.K.L.).
This work was supported by the National Institutes of Health [Grants R21-NS084007-01, R21NS096437-01, R01-NS NS086074, R01-092093, R01 NS108686-01 (to M.K.L., D.L., and A.A.), National Institute on Drug Abuse Training Grant T32 DA07234, Predoctoral Training Grant P32-GM008471 (to E.C.M.); and National Institute on Aging-funded predoctoral fellowship to T32-AG029796 to C.G.]; the Michael J. Fox Foundation; a UMN–Mayo partnership grant and a grant fromMinnesota Higher Education (D.L.); the Susan and David Plimpton Fund (M.K.L.). Behavioral studies were performed in the Mouse Behavioral Phenotyping Core at the University of Minnesota, which is supported by National Institute of Neurological Disorders and Stroke–NIH (Center Grant P30 NS062158).
© 2018, Society for Neuroscience. All rights reserved.
- AMPA receptor
- Frontotemporal dementia
- Parkinson’s disease
- Synaptic plasticity