Modulating dynamics and function of nuclear actin with synthetic bicyclic peptides.

Actin exists in monomeric globular (G-) and polymerized filamentous (F-) forms and the dynamics of its polymerization/depolymerization are tightly regulated in both the cytoplasm and the nucleus. Various essential functions of nuclear actin have been identified including regulation of gene expression and involvement in the repair of DNA double-strand breaks (DSB). Small G-actin-binding molecules affect F-actin formation and can be utilized for analysis and manipulation of actin in living cells. However, these G-actin-binding molecules are obtained by extraction from natural sources or through complex chemical synthesis procedures, and therefore, the generation of their derivatives for analytical tools is underdeveloped. In addition, their effects on nuclear actin cannot be separately evaluated from those on cytoplasmic actin. Previously, we have generated synthetic bicyclic peptides, consisting of two macrocyclic rings, which bind to G-actin but not to F-actin. Here, we describe the introduction of these bicyclic peptides into living cells. Furthermore, by conjugation to a nuclear localization signal (NLS), the bicyclic peptides accumulated in the nucleus. The NLS-bicyclic peptides repress the formation of nuclear F-actin, and impair transcriptional regulation and DSB repair. These observations highlight a potential role for NLS-linked bicyclic peptides in the manipulation of dynamics and functions of nuclear actin.

Impairment of nuclear F-actin formation and its relevance to cellular phenotypes in Hutchinson-Gilford progeria syndrome.

Hutchinson-Gilford progeria syndrome (HGPS) is a premature aging disorder caused by a mutation of lamin A, which contributes to nuclear architecture and the spatial organization of chromatin in the nucleus. The expression of a lamin A mutant, named progerin, leads to functional and structural disruption of nuclear organization. Since progerin lacks a part of the actin-binding site of lamin A, we hypothesized that nuclear actin dynamics and function are altered in HGPS cells. Nuclear F-actin is required for the organization of nuclear shape, transcriptional regulation, DNA damage repair, and activation of Wnt/ß-catenin signaling. Here we show that the expression of progerin decreases nuclear F-actin and impairs F-actin-regulated transcription. When nuclear F-actin levels are increased by overexpression of nuclear-targeted actin or by using jasplakinolide, a compound that stabilizes F-actin, the irregularity of nuclear shape and defects in gene expression can be reversed. These observations provide evidence for a novel relationship between nuclear actin and the etiology of HGPS.

[Case of obsessive-compulsive disorder associated with neuroleptics-induced deficit syndrome (NIDS): successfully treated by discontinuation of neuroleptics followed by SSRI].

A 59-year-old man, who was being trieated for schizophrenia, exhibited a concurrence of obsessive compulsive (OC) symptoms and neuroleptics-induced deficit syndrome (NIDS). His symptoms were remarkably improved by the discontinuation of neuroleptics followed by the introduction of fluvoxamine. He was originally a prudent, suspicious and unsociable person, the character of which corresponds to a schizotypal personality disorder. From his early twenties OC-symptoms appeared along the theme of cleanliness, health, and ethics. After the first half of his forties OC-symptoms worsened with the emergence of a depressive state. He consulted a psychiatric unit at the age of 49 for the first time and was diagnosed as having schizophrenia of a negative symptoms-dominant type associated with obsessive-compulsive disorder. He was started on haloperidol but the condition did not improved at all so that the dose was gradually increased. When he finally moved to our hospital at the age of 57, serious NIDS such as slow thinking, difficulty in concentration, decrease in emotional reaction, and dysphoria was recognized, in addition to parkinsonism. In order to improve the NIDS, we gradually decreased the dose and reduced the variety of neuroleptics and substituted them for risperidone alone. During these periods, no emergence of psychotic symptoms or worsening of OC-symptoms was realized. Accordingly he was admitted to our hospital and started on fluvoxamine, and the NIDS and OC-symptoms were markedly improved. In conclusion the use of neuroleptics specifically for OC-symptoms should be done very carefully in consideration of the possibility of provoking NIDS.