NMDA and AMPA Receptors at Synapses: Novel Targets for Tau and α-Synuclein Proteinopathies

Abstract

A prominent feature of neurodegenerative diseases is synaptic dysfunction and spine loss as early signs of neurodegeneration. In this context, accumulation of misfolded proteins has been identified as one of the most common causes driving synaptic toxicity at excitatory glutamatergic synapses. In particular, a great effort has been placed on dissecting the interplay between the toxic deposition of misfolded proteins and synaptic defects, looking for a possible causal relationship between them. Several studies have demonstrated that misfolded proteins could directly exert negative effects on synaptic compartments, altering either the function or the composition of pre- and post-synaptic receptors. In this review, we focused on the physiopathological role of tau and α-synuclein at the level of postsynaptic glutamate receptors. Tau is a microtubule-associated protein mainly expressed by central nervous system neurons where it exerts several physiological functions. In some cases, it undergoes aberrant post-translational modifications, including hyperphosphorylation, leading to loss of function and toxic aggregate formation. Similarly, aggregated species of the presynaptic protein α-synuclein play a key role in synucleinopathies, a group of neurological conditions that includes Parkinson's disease. Here, we discussed how tau and α-synuclein target the postsynaptic compartment of excitatory synapses and, specifically, AMPA- and NMDA-type glutamate receptors. Notably, recent studies have reported their direct functional interactions with these receptors, which in turn could contribute to the impaired glutamatergic transmission observed in many neurodegenerative diseases.

Keywords: AMPA receptors; NMDA receptors; dendritic spines; synaptic dysfunction; tau; α-synuclein.

Figure 2

Graphic representation of main human tau phosphosites and indications of the molecular events regulating their phosphorylation. Tau is composed of two main domains: a projection domain (resides Met1-Tyr197) and an assembly domain (Ser198-Leu441). The first includes the N-terminal extension and the first part of a proline-rich region (residues 165–197), and the latter the second part of the proline-rich region, three or four microtubule binding repeats (MTBR, numbered R1 to R4) and a C-terminal extension [4,5,9,14,20,39].

Figure 1

(A) Fyn localises to the postsynapse in a tau-dependent manner (1) where it associates with the postsynaptic density and phosphorylates GluN2B in the carboxy terminus domain (2). Since this phosphorylation facilitates the interaction of NMDARs with the scaffolding protein PSD-95 (3), Tau–Fyn interaction in spine increases the stability of NMDAR within the PSD [11]. (B) According to the Mondragón-Rodríguez model [12], the activation of NMDAR (1) leads to phosphorylation of tau by GSK3 (2). This phosphorylation strengthens the interaction between tau and Fyn (3), thus supporting a transient increase in NMDA receptor activation (4), but weakens the interaction between PSD95 and tau. As a result, Fyn finally leaves the PSD95-NMDA receptor complex (5).

Figure 3

Schematic representation of the secondary structure of the protein αsyn.