Biology subjects

Sokolov, M.

Publications and source records attributed to Sokolov, M..

3 recordsLinked to original sources

bioRxiv2026

Mapping the chaperonin TRiC/CCT interactome in mouse photoreceptors reveals functional significance for energy metabolism

The eukaryotic chaperonin TRiC/CCT is essential for folding a diverse set of proteins, yet its interactome and functional roles in specialized neurons remain incompletely understood. To investigate TRiC-mediated folding in rod photoreceptors, we generated a transgenic mouse line expressing an epitope-tagged Tcp-1 subunit, enabling purification of intact TRiC complexes from retinal tissue. Mass spectrometry identified 226 TRiC-interacting proteins, including known TRiC substrates and co-chaperones as well as numerous novel candidates enriched in RNA processing, cytoskeletal organization, and cell-cycle regulation. Using a TRiC loss-of-function model in which expression of a short splice isoform of phosducin-like protein (PhLPs) competitively inhibits TRiC activity, we observed marked reductions in canonical TRiC substrates, including tubulins, transducin {beta} subunits, and triosephosphate isomerase, as well as secondary alterations in proteins involved in cytoskeletal stability, membrane trafficking, energy metabolism, and phototransduction. Quantitative metabolomic profiling revealed that TRiC deficiency induces a metabolic "energy crisis" characterized by reduced glycolytic- and tricarboxylic acid cycle intermediates, acylcarnitines, ATP, NAD, and NADH, implicating widespread impairment of glucose utilization, mitochondrial bioenergetics, and fatty acid oxidation. Integrative proteomic-metabolomic analysis identified a small subset of proteins, including Rab10 and Anxa1, as potential drivers of these metabolic disruptions, with defective Rab10-dependent GLUT4 trafficking emerging as a plausible mechanism underlying impaired glucose uptake in TRiC-deficient rods. Finally, experiments using a perpetually unfolded G{beta}1 mutant and G{gamma}1-knockout mice demonstrated that substrate overload sequesters TRiC and competitively displaces other clients, exacerbating proteostasis imbalance. Together, our study provides a comprehensive in vivo mapping of the TRiC interactome in mammalian rods, reveals a connection between TRiC-dependent proteostasis and energy metabolism in rods, and indicates a mechanism by which misfolded TRiC substrates exacerbate a proteostasis imbalance that ultimately results in neurodegeneration.

biochemistry↗

bioRxiv2024

Self-driving development of perfusion processes for monoclonal antibody production

The development of autonomous agents in bioporcess development is crucial for advancing biopharma innovation, as it can significantly reduce the time and resources required to transition from product to process. While robotics and machine learning have greatly accelerated drug discovery and initial screening, the later stages of development have primarily benefited from experimental automation, lacking advanced computational tools for experimental planning and execution. For example, in the development of new monoclonal antibodies, the search for optimal upstream conditions (such as feeding strategy, pH, temperature, and media composition) is often conducted using sophisticated high-throughput (HT) mini-bioreactor systems, while the integration of machine learning tools for experimental design and operation in these systems have not matured accordingly. In this work, we introduce an integrated user-friendly software framework that combines a Bayesian experimental design algorithm, a cognitive digital twin of the cultivation system, and an advanced 24-parallel mini-bioreactor perfusion experimental setup. This results in an autonomous experimental machine capable of: (1) embedding existing process knowledge, (2) learning during experimentation, utilizing information from similar processes, (4) predicting future events, and (5) autonomously operating the parallel cultivation setup to achieve challenging objectives. As proof of concept, we present experimental results from 27-day-long cultivations operated by the autonomous software agent, which successfully achieved challenging goals such as increasing the viable cell volume (VCV) and maximizing the viability throughout the experiment.

bioengineering↗

bioRxiv2020

Spectrum of genes for inherited hearing loss in the Israeli Jewish population, including the novel human deafness gene ATOH1

Mutations in more than 150 genes are responsible for inherited hearing loss, with thousands of different, severe causal alleles that vary among populations. The Israeli Jewish population includes communities of diverse geographic origins, revealing a wide range of deafness-associated variants and enabling clinical characterization of the associated phenotypes. Our goal was to identify the genetic causes of inherited hearing loss in this population, and to determine relationships among genotype, phenotype, and ethnicity. Genomic DNA samples from informative relatives of 88 multiplex families, all of self-identified Jewish ancestry, with either non-syndromic or syndromic hearing loss, were sequenced for known and candidate deafness genes using the HEar-Seq gene panel. The genetic causes of hearing loss were identified for 60% of the families. One gene was encountered for the first time in human hearing loss: ATOH1 (Atonal), a basic helix-loop-helix transcription factor responsible for autosomal dominant progressive hearing loss in a five-generation family. Our results demonstrate that genomic sequencing with a gene panel dedicated to hearing loss is effective for genetic diagnoses in a diverse population. Comprehensive sequencing enables well-informed genetic counseling and clinical management by medical geneticists, otolaryngologists, audiologists, and speech therapists and can be integrated into newborn screening for deafness.

genetics↗