Biology subjects

Todorow, V.

Publications and source records attributed to Todorow, V..

4 recordsLinked to original sources

bioRxiv2025

Elimination of myotonia improves myopathy in a muscleblind knockout model of myotonic dystrophy

A cardinal sign of myotonic dystrophy type 1 (DM1) is slow of muscle relaxation after voluntary contraction known as myotonia. Myotonia results from mis-regulated splicing of chloride channel 1 (ClC-1), leading to loss of channel function and runs of involuntary action potentials in muscle fibers. Heralding the onset of weakness, myotonia is often the first symptom of DM1, and raising the possibility that muscle hyperexcitability promotes the subsequent development of myopathy. We used genome editing to test this possibility by deleting the alternatively spliced and frameshift inducing ClC-1 exon 7a (E7a) in the Mbnl1 knockout model of DM1. Although several ClC-1 exons exhibit mis-regulated splicing in DM1, deletion of this single cryptic exon was sufficient to restore ClC-1 function and eliminate myotonia systemically and permanently. As determined by long-read sequencing, deletion of E7a reduced the frequency of other splicing defects in ClC-1 transcripts, likely as a passive consequence of restoring reading frame and nonsense surveillance. Furthermore, we observed significantly improved muscle force generation, fiber-type distribution, and histology, and partial restoration of the muscle transcriptome, including differential gene expression and alternative splicing, in non-myotonic Mbnl1 knockout mice. These results suggest that E7a inclusion is a lynchpin splice event that contributes to skeletal myopathy, highlighting myotonia as a therapeutic target and an outcome of interest in DM1. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=171 SRC="FIGDIR/small/677400v1_ufig1.gif" ALT="Figure 1"> View larger version (44K): org.highwire.dtl.DTLVardef@101b333org.highwire.dtl.DTLVardef@9be92corg.highwire.dtl.DTLVardef@1e95c88org.highwire.dtl.DTLVardef@1b9eeee_HPS_FORMAT_FIGEXP M_FIG C_FIG

physiology↗

bioRxiv2025

Integrative Chemical Genetics Platform Identifies Condensate Modulators Linked to Neurological Disorders

Aberrant biomolecular condensates are implicated in neurological disorders including ALS, frontotemporal dementia, and DYT1 dystonia, yet approaches to systematically identify their modulators remain limited. Here we establish MLF2 as a versatile condensate biomarker and develop CondenScreen, an integrated high-content screening and bioinformatic pipeline enabling identification of condensate modulators across chemical and genetic space. Screening 1,760 FDA-approved compounds in a cellular DYT1 dystonia model, we identify drugs that alter aberrant condensate properties, validating the platform for condensate-targeted drug discovery. In parallel, a genome-wide CRISPR/Cas9 screen links condensate accumulation to microcephaly genes and more than 10 additional neurodevelopmental disorders. Machine learning and confocal imaging resolves distinct condensate phenotypes: loss of microcephaly-associated ZNF335 results in nucleoplasmic condensates, whereas RNF26 deletion produces nuclear envelope condensates that phenocopy hallmarks of torsin deficiency. Our study provides a scalable resource for identifying corrective modulators of condensates and establishes a link between nuclear condensate accumulation and neurodevelopmental disorders.

cell biology↗

bioRxiv2024

Nodal Modulator (NOMO) is a force-bearing transmembrane protein required for muscle differentiation

The endoplasmic reticulum (ER) relies on specialized membrane-shaping proteins to maintain a continuous network of sheets and tubules that host distinct biological processes. How this intricate structure of the ER membrane system is maintained under conditions of mechanical strain is incompletely understood. NOMO is an ER-resident transmembrane protein that contributes to ER morphology and is highly expressed in striated muscle. In this study, we identify a critical interface between distal Ig domains that enables NOMO to maintain ER morphology and buffer mechanical forces. By incorporating two independent tension sensors in the luminal domain of NOMO, we demonstrate that NOMO assemblies experience forces in the single piconewton (pN) range, with a significant contribution from the identified interface. These newly defined features are important, if not indispensable, for myogenesis, as interface mutations affecting mechanosensing fail to restore the essential role of NOMO during myogenesis in a C2C12 differentiation model. Moreover, NOMO depletion impairs nematode motility, underscoring a broader functional importance in muscle physiology.

cell biology↗

bioRxiv2022

Metabolic, Fibrotic, and Splicing Pathways Are All Altered in Emery-Dreifuss Muscular Dystrophy Spectrum Patients to Differing Degrees

Emery-Dreifuss muscular dystrophy (EDMD) is a genetically and clinically variable disorder. Previous attempts to use gene expression changes find its pathomechanism were unavailing, so we here engaged a functional pathway analysis. RNA-Seq was performed on cells from 10 patients diagnosed with an EDMD spectrum disease with different mutations in 7 genes. Upon comparing to controls, the pathway analysis revealed that multiple genes involved in fibrosis, metabolism, myogenic signaling, and splicing were affected in all patients. Splice variant analysis revealed alterations of muscle-specific variants for several important muscle genes. Deeper analysis of metabolic pathways revealed a reduction in glycolytic and oxidative metabolism and reduced numbers of mitochondria across a larger set of 14 EDMD patients and 7 controls. Intriguingly, the gene expression signatures segregated the patients into three subgroups whose distinctions could potentially relate to differences in clinical presentation. Finally, differential expression analysis of miRNAs changing in the patients similarly highlighted fibrosis, metabolism, and myogenic signaling pathways. This pathway approach revealed a clear EDMD signature that can both be used as the basis for establishing a biomarker panel specific to EDMD and direct further investigation into its pathomechanism. Furthermore, the segregation of specific gene changes into three distinct categories that appear to correlate with clinical presentation may be developed into prognostic biomarkers, though this will first require their testing in a wider set of patients with more clinical information.

genetics↗