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. The WT peptides were round and well dispersed, while mutants were inhomogeneous and disrupted to form dimer to trimer that aligned along one direction without apparent aggregate formation. Homozygous L604F mutant mice created by CRISPR exhibited the significant decrease in DISC1 level in the immunohistopathology at the hippocampal region compared to the WTs. The ratio of prepulse inhibition of the homozygous mutant mice was significantly impaired compared to WTs. Altered DISC1 distribution or function caused by aberrant intermolecular interactions may contribute to information processing characteristics in schizophrenia.

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

Prion diseases are fatal neurodegenerative diseases associated with structural conversion of α-helical prion protein (PrP) into its ß-sheet rich isoform (PrPSc). 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-ß 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. Interestingly, although most of the mutations had little or no effect on the biochemical properties of PrP, the V210K mutation induced structural conversion of PrP into a ß-structure. The ß-inducing effect was prominent and observed even under a physiological condition (i.e., in the absence of denaturant, acidic pH, reducing agent, and high temperature) in contrast to the disease-associated mutations in the PrP gene. We also examined structural features of V210K PrP using guanidine-hydrochloride unfolding, dynamic light scattering, 8-anilino-1-naphthalene sulfonate fluorescence, and electron microscopy, and revealed that V210K PrP assembles into a non-fibrillar ß-rich oligomer. Thus, the α-to-ß conversion can be induced by introduction of a charged residue into the hydrophobic core, which provide novel insight into the structural dynamics of PrP.