Patient fibroblast circadian rhythms predict lithium sensitivity in bipolar disorder.

Bipolar disorder is a chronic neuropsychiatric condition associated with mood instability, where patients present significant sleep and circadian rhythm abnormalities. Currently, the pathophysiology of bipolar disorder remains elusive, but treatment with lithium continues as the benchmark pharmacotherapy, functioning as a potent mood stabilizer in most, but not all patients. Lithium is well documented to induce period lengthening and amplitude enhancement of the circadian clock. Based on this, we sought to investigate whether lithium differentially impacts circadian rhythms in bipolar patient cell lines and crucially if lithium's effect on the clock is fundamental to its mood-stabilizing effects. We analyzed the circadian rhythms of bipolar patient-derived fibroblasts (n = 39) and their responses to lithium and three further chronomodulators. Here we show, relative to controls (n = 23), patients exhibited a wider distribution of circadian period (p < 0.05), and that patients with longer periods were medicated with a wider range of drugs, suggesting lower effectiveness of lithium. In agreement, patient fibroblasts with longer periods displayed muted circadian responses to lithium as well as to other chronomodulators that phenocopy lithium. These results show that lithium differentially impacts the circadian system in a patient-specific manner and its effect is dependent on the patient's circadian phenotype. We also found that lithium-induced behavioral changes in mice were phenocopied by modulation of the circadian system with drugs that target the clock, and that a dysfunctional clock ablates this response. Thus, chronomodulatory compounds offer a promising route to a novel treatment paradigm. These findings, upon larger-scale validation, could facilitate the implementation of a personalized approach for mood stabilization.

Single-Cell Sequencing of iPSC-Dopamine Neurons Reconstructs Disease Progression and Identifies HDAC4 as a Regulator of Parkinson Cell Phenotypes.

Induced pluripotent stem cell (iPSC)-derived dopamine neurons provide an opportunity to model Parkinson's disease (PD), but neuronal cultures are confounded by asynchronous and heterogeneous appearance of disease phenotypes in vitro. Using high-resolution, single-cell transcriptomic analyses of iPSC-derived dopamine neurons carrying the GBA-N370S PD risk variant, we identified a progressive axis of gene expression variation leading to endoplasmic reticulum stress. Pseudotime analysis of genes differentially expressed (DE) along this axis identified the transcriptional repressor histone deacetylase 4 (HDAC4) as an upstream regulator of disease progression. HDAC4 was mislocalized to the nucleus in PD iPSC-derived dopamine neurons and repressed genes early in the disease axis, leading to late deficits in protein homeostasis. Treatment of iPSC-derived dopamine neurons with HDAC4-modulating compounds upregulated genes early in the DE axis and corrected PD-related cellular phenotypes. Our study demonstrates how single-cell transcriptomics can exploit cellular heterogeneity to reveal disease mechanisms and identify therapeutic targets.

Type 1 insulin-like growth factor receptor translocates to the nucleus of human tumor cells.

The type 1 insulin-like growth factor receptor (IGF-1R) is a transmembrane glycoprotein composed of two extracellular alpha subunits and two beta subunits with tyrosine kinase activity. The IGF-1R is frequently upregulated in cancers and signals from the cell surface to promote proliferation and cell survival. Recent attention has focused on the IGF-1R as a target for cancer treatment. Here, we report that the nuclei of human tumor cells contain IGF-1R, detectable using multiple antibodies to alpha- and beta-subunit domains. Cell-surface IGF-1R translocates to the nucleus following clathrin-mediated endocytosis, regulated by IGF levels. The IGF-1R is unusual among transmembrane receptors that undergo nuclear import, in that both alpha and beta subunits traffic to the nucleus. Nuclear IGF-1R is phosphorylated in response to ligand and undergoes IGF-induced interaction with chromatin, suggesting direct engagement in transcriptional regulation. The IGF dependence of these phenomena indicates a requirement for the receptor kinase, and indeed, IGF-1R nuclear import and chromatin binding can be blocked by a novel IGF-1R kinase inhibitor. Nuclear IGF-1R is detectable in primary renal cancer cells, formalin-fixed tumors, preinvasive lesions in the breast, and nonmalignant tissues characterized by a high proliferation rate. In clear cell renal cancer, nuclear IGF-1R is associated with adverse prognosis. Our findings suggest that IGF-1R nuclear import has biological significance, may contribute directly to IGF-1R function, and may influence the efficacy of IGF-1R inhibitory drugs.