A peptide mimetic therapeutic strategy targeting dysfunction of the scaffold protein DISC-1 in psychiatric disorders

Disrupted in schizophrenia 1 (DISC1) is a scaffold protein that regulates several physiological processes ranging from cellular division to neurodevelopment, and its dysfunction contributes to various neurological disorders including schizophrenia, bipolar and mood disorders, and autism. Thus, deciphering its native functions and pathophysiological roles is crucial. In this report, three disease-associated mutants of the C-region of DISC1, i.e., S713E, S704C, and L807-frameshift, were examined to further elucidate the role of DISC1 in cell division. We demonstrate that the mutations do not render the variants functionally inactive; instead, the interaction sites are presumably lost during the aggregation of the DISC1 C-region into amyloid-type fibrils. The minimal fibrillizing element in the C-region is the intrinsically disordered β-core (716‒761) that houses a segment absent in the splice variant DISC1^Δ22aa, which cannot bind proteins of the mitotic spindle complex and thus hampers cellular proliferation. Based on these structure-function relationships, we present a rational drug development strategy using phage display technology and highlight the role of peptide mimetics in curtailing the agglomeration of fibrils.