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

Abstract

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.

Pathological α-synuclein triggers synaptic NMDA receptor dysfunction through altered trafficking

“…However, the mechanism through which α-syn abnormalities affect synaptic transmission remains unclear. Our ndings are consistent with recent ndings that pathological α-syn (i.e., A53T-and α-syn PFF) downregulates NMDAR synaptic content and functions [10,11,25,34,47]. Our study provides direct molecular evidence that pathological α-syn rapidly alters NMDAR tra cking, which affects the NMDAR synaptic content.…”

“…Moreover, it has been shown to cause severe movement disorders in A53T transgenic mice [45,46] and to be involved in early-onset familial PD [44]. Furthermore, it has been recently shown to cause learning, memory, and synaptic plasticity de cits [47,48]; speci cally, only A53T-mutant, but not WT-or A30P-mutant, α-syn can induce postsynaptic dysfunction in transgenic mice [47]. Consequently, we assessed whether A53T-α-syn could alter NMDAR membrane tra cking and synaptic content.…”

“…Synaptic dysfunctions could re ect early events in synucleinopathies before neuronal death [10,47,48,58]. Therefore, there is a need to understand the molecular mechanism(s) underlying this early effect on synapses.…”

“…Recent studies have shown that postsynaptic dysfunction is a crucial process correlated with cognitive impairment and dementia in synucleinopathies [47,48,59]. Moreover, dendritic spine loss and compromised neuronal and network activities have been observed before neuronal death after exposure to extracellular α-syn (e.g.…”

“…There is increasing evidence that A53T-α-syn, but not WT-α-syn or other mutations, induces postsynaptic impairment [47,48], α-syn inclusion, [45,61] and neurotoxicity [45,46]. Furthermore, individuals with A53T mutation developed a severe PD that is often associated with dementia [62].…”