Hyperactivity and attention deficits in mice with decreased levels of stress inducible phosphoprotein 1 (STIP1)

Abstract

Stress-inducible phosphoprotein I (STIP1, STI1 or HOP) is a co-chaperone intermediating Hsp70/Hsp90 exchange of client proteins, but it can also be secreted to trigger prion protein-mediated neuronal signaling. Some mothers of children with autism spectrum disorders (ASD) present antibodies against certain brain proteins, including antibodies against STIP1. Maternal antibodies can cross the fetus blood-brain barrier during pregnancy, suggesting the possibility that they can interfere with STIP1 levels and, presumably, functions. However, it is currently unknown whether abnormal levels of STIP1 have any impact in ASD-related behavior. Here, we used mice with reduced (50%) or increased STIP1 levels (fivefold) to test for potential ASD-like phenotypes. We found that increased STIP1 regulates the abundance of Hsp70 and Hsp90, whereas reduced STIP1 does not affect Hsp70, Hsp90 or the prion protein. Interestingly, BAC transgenic mice presenting fivefold more STIP1 show no major phenotype when examined in a series of behavioral tasks, including locomotor activity, elevated plus maze, Morris water maze and five-choice serial reaction time task (5-CSRTT). In contrast, mice with reduced STIP1 levels are hyperactive and have attentional deficits on the 5-CSRTT, but exhibit normal performance for the other tasks. We conclude that reduced STIP1 levels can contribute to phenotypes related to ASD. However, future experiments are needed to define whether it is decreased chaperone capacity or impaired prion protein signaling that contributes to these phenotypes.

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“…In addition, we found some common proteins that were differentially expressed among the four comparison groups ( Figure S1A and Tables S1–4 ). These differential proteins included signaling protein high-mobility group protein B1 (HMGB1) a mediator of neurite degeneration through the identification of the pathological signaling pathway in AD [ 13 ]; molecular chaperones (heat shock cognate 71 kDa protein (HSP7C)), a molecular chaperone and a member of the heat shock protein family that plays an integral role in the stress response [ 14 ]; translationally controlled tumor protein (TCTP), which has critical roles in the defense against oxidative and thermal stresses [ 15 ] (shown in Table S1 ); endoplasmic reticulum (ER) stress-associated protein (protein disulfide-isomerase A6 (PDIA6)), a protein related to ER stress that plays a critical role in most biological processes [ 16 ]; oxidative stress-associated protein (D-3-phosphoglycerate dehydrogenase (SERA)), a protein involved in the metabolism and development of the central nervous system [ 17 ]; cytoskeleton-associated protein (peripherin (PERI)), a type III intermediate filament (IF) protein that plays a contributory role in motor neuron disease [ 18 , 19 ]; molecular chaperone (stress-induced-phosphoprotein 1 (STIP1)), a cochaperone intermediating Hsp70/Hsp90 exchange of client proteins and involved in prion protein-mediated neuronal signaling [ 20 ] (shown in Table S2 ); and cytoskeleton-associated protein (TPIS) (shown in Table S3 ). We found that two proteins, namely, isocitrate dehydrogenase [NADP] cytoplasmic (IDHC), which plays important roles in energy and biosynthesis metabolisms [ 21 ], and eukaryotic translation initiation factor 1b (EIF1B), an antiapoptotic protein that protects cells uniquely from Fas-induced apoptosis [ 22 ], were commonly changed in various concentrations of DAU-treated N2a/APP cells compared with the vehicle-treated N2a/APP cells (shown in Figure S1B and Table S8 ).…”

Seeking for potential pathogenic genes of major depressive disorder in the Gene Expression Omnibus database

“…Braunschweig et al has identified six brain proteins as targets for autism spectrum disorders antibodies, including STIP1 (Beraldo et al, ). Moreover, some mothers of children with autism spectrum disorders present antibodies against STIP1 (Beraldo et al, ). It is suggested that down‐regulated STIP1 levels may contribute to autism spectrum disorders (Beraldo et al, ).…”

“…Moreover, some mothers of children with autism spectrum disorders present antibodies against STIP1 (Beraldo et al, ). It is suggested that down‐regulated STIP1 levels may contribute to autism spectrum disorders (Beraldo et al, ). In addition, it is found that STIP1 is differentially expressed and involved in cell communication or signaling in patients with MDD (Martins‐de‐Souza et al, ).…”

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“…STIP1 is a major ligand of the cellular prion protein (PrP(C)) and together they mediate neuritogenesis in cultured hippocampal neurons [ 41 , 42 ]. Inhibition of this interaction leads to impaired memory formation in rodents [ 43 ], while a STIP1 50% reduction produces ASD-like phenotypes in mice, including hyperactive and attentional deficits [ 44 ]. STIP1 also modulates proliferation of astrocytes and retinal cells, and is associated with glioblastoma [ 45 – 47 ].…”