A DISC1 point mutation promotes oligomerization and impairs information processing in a mouse model of schizophrenia.

Disrupted-in-schizophrenia 1 (DISC1) is strongly associated with schizophrenia, but it remains elusive how the modification of the intermolecular interaction of DISC1 affects the information processing in brain. We show that a DISC1 point mutation alters intermolecular cohesiveness promoting the phase separation, and disrupts sensorimotor gating monitored by the prepulse inhibition in a mouse model of schizophrenia. Although the conformation of DISC1 partial peptide with the schizophrenia-related mutation L607F in human or the corresponding L604F in mouse was essentially indistinguishable from the wild type (WT) as long as monitored by fluorescence, circular dichroism, ultracentrifugation, dynamic light scattering and nuclear magnetic resonance, the atomic force microscopy was able to detect their morphological distinctions.

A valine-to-lysine substitution at position 210 induces structural conversion of prion protein into a β-sheet rich oligomer.

Prion diseases are fatal neurodegenerative diseases associated with structural conversion of α-helical prion protein (PrP) into its β-sheet rich isoform (PrP). Previous genetic analyses have indicated that several amino acid residues involved in the hydrophobic core of PrP (such as V180, F198, and V210) play a critical role in the development of prion diseases. To understand how these hydrophobic residues would contribute to the α-to-β conversion process of PrP, we substituted the V210 residue with bulkier (V210F, V210I, and V210L), smaller (V210A), and charged amino acids (V210K) and characterized its effects.