Abstract
Signaling between neurons in the human central nervous system (CNS) is accomplished through a highly interconnected network of presynaptic and postsynaptic elements essential in the conveyance of electrical and neurochemical information. One recently characterized core postsynaptic element essential to the efficient operation of this complex network is a relatively abundant ~184.7 kDa proline-rich synapse-associated cytoskeletal protein known as Shank3 (SH3-ankyrin repeat domain; encoded at human chr 22q13.33). In this “Perspectives” article, we review and comment on current advances in Shank3 research and include some original data that show common Shank3 deficits in a number of seemingly unrelated human neurological disorders that include sporadic Alzheimer’s disease (AD), autism spectrum disorder (ASD), bipolar disorder (BD), Phelan–McDermid syndrome (PMS; 22q13.3 deletion syndrome), and schizophrenia (SZ). Shank3 was also found to be downregulated in the CNS of the transgenic AD (TgAD) 5x familial Alzheimer’s disease murine model engineered to overexpress the 42 amino acid amyloid-beta (Aβ42) peptide. Interestingly, the application of known pro-inflammatory stressors, such as the Aβ42 peptide and the metal-neurotoxin aluminum sulfate, to human neuronal–glial cells in primary culture resulted in a significant decrease in the expression of Shank3. These data indicate that deficits in Shank3-expression may be one common denominator linking a wide-range of human neurological disorders that exhibit a progressive or developmental synaptic disorganization that is temporally associated with cognitive decline.
Highlights
Reviewed by: Alessandro Bertoli, Università degli Studi di Padova, Italy Carlo Sala, Istituto di Neuroscienze (CNR), Italy
In this “Perspectives” article, we review and comment on current advances in Shank3 research and include some original data that show common Shank3 deficits in a number of seemingly unrelated human neurological disorders that include sporadic Alzheimer’s disease (AD), autism spectrum disorder (ASD), bipolar disorder (BD), Phelan–McDermid syndrome (PMS; 22q13.3 deletion syndrome), and schizophrenia (SZ)
Different Shank3 protein isoforms are alternately expressed according to brain region, cell type, and developmental stage; for example, (i) all five major Shank3 isoforms (Shank 3A-3E) are highly abundant in mouse hippocampal neurons throughout development and aging [1,2,3, 7]; (ii) full length human Shank3 (1,731 amino acids; 184,667 Da) contains six highly interactive domains in tandem conducive to engagement in multiple protein–protein interactions at the postsynaptic density (PSD) [1,2,3,4]; (iii) posttranscriptional regulation of Shank3 expression may be mediated by microRNAs, such as miRNA-34a, that itself has been implicated in multiple neuropsychiatric disorders involving synaptic disruption [8,9,10,11]; and (iv) Shank3 possesses a remarkably complex interactome, conducive to Shank3’s role as a master organizer of a highly interconnected synaptic and cytoskeletal network [12,13,14,15,16,17]
Summary
Reviewed by: Alessandro Bertoli, Università degli Studi di Padova, Italy Carlo Sala, Istituto di Neuroscienze (CNR), Italy.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
