Phosphorylation in two discrete tau domains regulates a stepwise process leading to postsynaptic dysfunction.

KEY POINTS: Tau mislocalization to dendritic spines and associated postsynaptic deficits are mediated through different and non-overlapping phosphorylation sites. Tau mislocalization to dendritic spines depends upon the phosphorylation of either Ser396 or Ser404 in the C-terminus. Postsynaptic dysfunction instead depends upon the phosphorylation of at least one of five residues in the proline-rich region of tau. The blockade of both glycogen synthetase kinase 3ß and cyclin-dependent kinase 5 is required to prevent P301L-induced tau mislocalization to dendritic spines, supporting redundant pathways that control tau mislocalization to spines. ABSTRACT: Tau protein consists of an N-terminal projection domain, a microtubule-binding domain and a C-terminal domain. In neurodegenerative diseases, including Alzheimer's disease and frontotemporal dementia, the hyperphosphorylation of tau changes its shape, binding partners and resulting function. An early consequence of tau phosphorylation by proline-directed kinases is postsynaptic dysfunction associated with the mislocalization of tau to dendritic spines. The specific phosphorylation sites leading to these abnormalities have not been elucidated. Here, using imaging and electrophysiological techniques to study cultured rat hippocampal neurons, we show that postsynaptic dysfunction results from a sequential process involving differential phosphorylation in the N-terminal and C-terminal domains. First, tau mislocalizes to dendritic spines, in a manner that depends upon the phosphorylation of either Ser396 or Ser404 in the C-terminal domain. The blockade of both glycogen synthetase kinase 3ß and cyclin-dependent kinase 5 prevents tau mislocalization to dendritic spines. Second, a reduction of functional AMPA receptors depends upon the phosphorylation of at least one of five residues (Ser202, Thr205, Thr212, Thr217 and Thr231) in the proline-rich region of the N-terminal domain. This is the first report of differential phosphorylation in distinct tau domains governing separate, but linked, steps leading to synaptic dysfunction.

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

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 3ß-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.