The role of postsynaptic density proteins in neural degeneration and regeneration

Abstract

The structure, function and plasticity of excitatory glutamatergic synapses in the brain are significantly altered by neurodevelopmental and neurodegenerative disorders (Grabrucker et al., 2011; Fourie et al., 2014; Musardo et al., 2014; Lee et al., 2015), resulting in impairments in cognition, learning, memory, motor and sensory function. Reversing these synaptic deficits is a major challenge for neuroscience, and significant research has focussed on glutamate receptors as therapeutic targets but human trials have shown little success. Recently, attention has turned to proteins localized to the postsynaptic density (PSD) of excitatory synapses, as these proteins control the trafficking and targeting of glutamate receptors at synapses. Not surprisingly, PSD proteins have been shown to be altered in human and rodent models of neurological disorders, suggesting changes in their expression during the disease process (Grabrucker et al., 2011; Fourie et al., 2014; Musardo et al., 2014; Mei et al., 2016). However, the sheer number of these proteins, each with unique splice variations and developmental expression profiles, raises the possibility that targeted expression of specific PSD protein subfamilies within defined time windows has significant therapeutic potential. Indeed rescue of normal social behaviour has recently been observed in adulthood in an autism rodent model by re-expression of SHANK3, which encodes a major PSD protein, yet rescue of anxiety and motor coordination deficits required SHANK3 re-expression earlier in development (Mei et al., 2016). Peptide disruption of PSD protein interactions with glutamate receptors is also showing promise to reduce excitotoxicity and ischaemic damage in stroke models (Zhou et al., 2015). Increasing our knowledge of the potential of these proteins in human neurons is the next important step, as this will be key to determining their true therapeutic potential for neuroregeneration.