Pathological role of tau in α-synuclein dependent synaptic and memory deficits

Identification: Singh, Balvindar


Description

Pathological role of tau in α-synuclein dependent synaptic and memory deficits
 
Balvindar Singh1,2, Ana Covelo3, Peter Teravskis3, Michael Benneyworth3,4, Héctor M. Martinez3, Dezhi Liao3,4, Alfonso Araque3,4, Michael K. Lee3,4,5
1Medical Scientist Training Program; 2Graduate Program in Neuroscience; 3Department of Neuroscience; 4Institute for Translational Neuroscience; University of Minnesota; 5GRECC; Minneapolis VA Health Care System
 
Parkinson's disease (PD) is classically characterized by motor dysfunction due to dopaminergic (DA) neuron degeneration in the substantia nigra pars compacta. However, DA-independent, non-motor dysfunction adversely impacts patient quality of life. In particular, cognitive impairment and dementia are prominent disease features. Because mutations in the ⍺-synuclein (⍺S) gene cause familial autosomal dominant PD, ⍺S abnormalities are linked to neuronal dysfunction and neurodegeneration in PD. Further, the current view suggests that cognitive deficits in PD are due to pathological effects of ⍺S abnormalities in forebrain regions. Herein, we show that human missense A53T mutant ⍺S impairs synaptic function, synaptic plasticity, and memory prior to overt neurodegeneration. In particular, while ⍺S is an established modulator of presynaptic neurobiology, we demonstrate that A53T ⍺S uniquely causes cell autonomous deficits in postsynaptic function. Further, mutant ⍺S-induced postsynaptic changes require phosphorylation-dependent tau mislocalization into dendritic spines, leading to AMPA receptor internalization and subsequent impairments in neuronal activity observed both in vitro and ex vivo. To translate the significance of our findings, we determined whether mutant ⍺S-dependent cognitive deficits in the transgenic mouse model of ⍺-synucleinopathy (TgA53T) require endogenous tau expression. Our results show that the lack of tau expression in TgA53T mice completely blocks the onset of cognitive deficits in this model. Consistent with these behavioral results, in vitro dissociated neuronal culture and ex vivo hippocampal slice studies show that loss of endogenous tau expression reverses functional deficits caused by mutant ⍺S. In summary, we show that ⍺S abnormalities cause postsynaptic deficits that directly implicate tau as a mediator of ⍺S-induced memory changes.
 
Funding: R21-NS084007-01, R21-NS096437-01, Michael J. Fox Foundation grant (DL); R01-NS NS086074, R01-092093, Susan and David Plimpton Fund (MKL)
 

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