*2.4. TRIOBP-1 in Mental Illness*

It has recently been suggested that chronic mental illnesses such as schizophrenia, bipolar disorder, and major depression may be caused in part by the accumulation of aggregates of specific proteins in the brains of patients [34,35], in partial analogy to similar insoluble protein deposits in neurodegenerative conditions. In order to detect such proteins, the total insoluble (and aggregated) protein fraction was isolated from the brains of patients with schizophrenia, and used to inoculate a mouse. Monoclonal antibodies were generated from this animal and screened for the ability to specifically recognize the insoluble protein fraction of the patient brain compared to an equivalent preparation from the control brain tissue [36]. One such antibody was found to recognize TRIOBP-1, suggesting it to be present in an aggregated state in the brains of at least a subgroup of patients [23].

TRIOBP-1, but not TRIOBP-4, formed insoluble aggregates when expressed in mammalian cell culture or rodent primary neurons [23]. Subsequent mapping studies determined the central CC region of TRIOBP-1 to be the basis of its aggregation propensity [12]. The critical region for aggregation has now been mapped to a 25 amino acid long loop containing multiple charged amino acids [12]. In addition to 70 kDa full length TRIOBP-1, aggregation is also seen of shorter (45–60 kDa) protein species, representing coiled-coil regions of TRIOBP-1, but without the PH domain [23]. The consequences of TRIOBP-1 aggregation are still being determined, although effects have been seen on neurite outgrowth in cell culture [23]. Structures resembling aggregates have also been seen when TRIOBP-1 is expressed in other tissues [15,20]. Regulation of *TRIOBP* expression and folding may therefore be important for mental health. One such regulatory factor is already known, the ubiquitin ligase HECTD3, which leads to degradation of TRIOBP-1 [32].

Unlike several other proteins that are implicated as aggregating in mental illness [35], TRIOBP-1 is not encoded for by a known genetic risk factor for major mental illness. This may be because the functions of TRIOBP-1 in actin regulation are fundamental to life, and as such, mutations in its (highly conserved) sequence would lead to outcomes more detrimental than those seen in mental illness. Supporting evidence comes from a handful of studies, however. First, in two screens of samples from separate brain banks, levels of *TRIOBP* transcripts were seen to be subtly, but significantly higher in schizophrenia patients than in the controls [37]. Second, a polymorphism in the *NDE1*/*miR-484* locus, previously associated with schizophrenia in the Finnish population [38], was found to affect the expression of *TRIOBP* transcripts [39,40]. *MiR-484* expression was subsequently shown to lead to increased levels of the TRIOBP-1 protein [40]. Finally, a consanguineous family has been reported who suffer from schizophrenia, epilepsy, and hearing, with linkage to chromosome 22q12.3 q13.3 [41]. It is therefore possible, although not yet verified, that rare variants in *TRIOBP* could be responsible for these phenotypes.
