Biology subjects

Jarnik, M.

Publications and source records attributed to Jarnik, M..

6 recordsLinked to original sources

bioRxiv2025

Non-synaptic Mechanism of Ocular Dominance Plasticity

Classic experiments showing that monocular visual disruption alters synaptic connections to binocular neurons established the fundamental concept of synaptic plasticity. Synaptic inputs that are activated coincidently with postsynaptic action potential firing are strengthened, and inputs from cells firing before or after the postsynaptic action potential are weakened. An implicit assumption, however, is that the speed of impulse transmission is not altered by visual deprivation. If so, spike time arrival at binocular neurons would be affected, thereby inducing synaptic plasticity. This possibility is tested here in adult mice by monocular eyelid suture and monocular action potential inhibition in retinal axons. The results show that spike time arrival in visual cortex is altered by monocular visual disruption in association with morphological changes in myelin (nodes of Ranvier) on axons in optic nerve and optic tract. This non-synaptic mechanism of ocular dominance plasticity, mediated by myelin-forming cells, supplements and may drive synaptic plasticity.

neuroscience↗

bioRxiv2025

CHIP protects lysosomes from CLN4 mutant-induced membrane damages

Understanding how cells mitigate lysosomal damage is critical for unraveling pathogenic mechanisms of lysosome-related diseases. Here we use organelle-specific proteomics in iPSC-derived neurons (i3Neuron) and an in vitro lysosome-damaging assay to demonstrate that lysosome damage, caused by the aggregation of Ceroid Lipofuscinosis Neuronal 4 (CLN4)-linked DNAJC5 mutants on lysosomal membranes, serves as a critical pathogenic linchpin in CLN4-associated neurodegeneration. Intriguingly, in non-neuronal cells, a ubiquitin-dependent microautophagy mechanism downregulates CLN4 aggregates to counteract CLN4-associated lysotoxicity. Genome-wide CRISPR screens identify the ubiquitin ligase CHIP as a central microautophagy regulator that confers ubiquitin-dependent lysosome protection. Importantly, CHIPs lysosome protection function is transferrable, as ectopic CHIP improves lysosomal function in CLN4 i3Neurons, and effectively alleviates lipofuscin accumulation and neurodegeneration in a Drosophila CLN4 disease model. Our study establishes CHIP-mediated microautophagy as a key organelle damage guardian that preserves lysosome integrity, offering new insights into therapeutic development for CLN4 and other lysosome-related neurodegenerative diseases.

cell biology↗

bioRxiv2021

σ28-dependent small RNAs regulate timing of flagella biosynthesis

Flagella are important for bacterial motility as well as for pathogenesis. Synthesis of these structures is energy intensive and, while extensive transcriptional regulation has been described, little is known about the posttranscriptional regulation. Small RNAs (sRNAs) are widespread posttranscriptional regulators, most base pairing with mRNAs to affect their stability and/or translation. Here we describe four UTR-derived sRNAs (UhpU, MotR, FliX and FlgO) whose expression is controlled by the flagella sigma factor {sigma}28 (fliA) in Escherichia coli. Interestingly, the four sRNAs have varied effects on flagellin protein levels, flagella number and cell motility. UhpU, corresponding to the 3 UTR of a metabolic gene, likely has hundreds of targets including a transcriptional regulator at the top flagella regulatory cascade connecting metabolism and flagella synthesis. Unlike most sRNAs, MotR and FliX base pair within the coding sequences of target mRNAs and act on ribosomal protein mRNAs connecting ribosome production and flagella synthesis. The study shows how sRNA-mediated regulation can overlay a complex network enabling nuanced control of flagella synthesis.

microbiology↗

bioRxiv2020

A Myosin-7B dependent endocytosis pathway mediates cellular entry of α-Synuclein fibrils and polycation-bearing cargos

Cell-to-cell transmission of misfolding-prone -Synuclein (-Syn) has emerged as a key pathological event in Parkinsons disease. This process is initiated when -Syn-bearing fibrils enter cells via clathrin-mediated endocytosis, but the underlying mechanisms are unclear. Using a CRISPR-mediated knockout screen, we identify SLC35B2 and Myosin-7B (MYO7B) as critical endocytosis regulators for -Syn preformed fibrils (PFF). We show that SLC35B2, as a key regulator of heparan sulfate proteoglycan (HSPG) biosynthesis, is essential for recruiting -Syn PFF to the cell surface because this process is mediated by interactions between negatively charged sugar moieties of HSPGs and clustered K-T-K motifs in -Syn PFF. By contrast, MYO7B regulates -Syn PFF entry by maintaining a plasma-membrane-associated actin network that controls membrane dynamics. Without MYO7B or actin filaments, many clathrin-coated pits fail to be severed from the membrane, causing accumulation of large clathrin-containing scars on the cell surface. Intriguingly, the requirement for MYO7B in endocytosis is only restricted to -Syn PFF and other cargos that enter cells via HSPGs. Thus, by identifying new regulatory factors for -Syn PFF endocytosis, our study defines a mechanistically distinct clathrin-mediated endocytosis pathway that requires additional force generated by MYO7B and actin filaments. SignificanceThe spreading of misfolded protein aggregates such as -Synuclein preformed fibrils (-Syn PFF) from cell to cell is a pathologic hallmark associated with the progression of many neurodegenerative diseases, but it is unclear how mammalian cells take up these large protein aggregates to initiate this prion-like protein transmission process. Here we define the mechanism of -Syn PFF endocytosis using a combination of genetic, biochemical, and live-cell imaging techniques. Our study reveals how -Syn PFF binds to the cell surface heparan sulfate proteoglycans using two lysine-bearing motifs and then enters cells following a Myosin-7B- and actin-dependent endocytosis mechanism that is specifically tailored for polycation-bearing cargos.

cell biology↗

bioRxiv2019

Neto-α controls synapse organization and homeostasis at the Drosophila neuromuscular junction

Glutamate receptor auxiliary proteins control receptor distribution and function, ultimately controlling synapse assembly, maturation and plasticity. At the Drosophila neuromuscular junction (NMJ), a synapse with both pre- and post-synaptic kainate-type glutamate receptors (KARs), we show that the auxiliary protein Neto evolved functionally distinct isoforms to modulate synapse development and homeostasis. Using genetics, cell biology and electrophysiology we demonstrate that Neto- functions on both sides of the NMJ. In muscle, Neto- limits the size of the postsynaptic receptors field. In motor neurons, Neto- controls neurotransmitter release in a KAR-dependent manner. Furthermore, Neto- is both required and sufficient for the presynaptic increase in neurotransmitter release in response to reduced postsynaptic sensitivity. This KAR-independent function of Neto- is involved in activity-induced cytomatrix remodeling. We propose that Drosophila ensured NMJ functionality by acquiring two Neto isoforms with differential expression patterns and activities.

neuroscience↗

bioRxiv2019

IRBIT Directs Differentiation of Intestinal Stem Cell Progeny to Maintain Tissue Homeostasis

The maintenance of the intestinal epithelium is ensured by the controlled proliferation of intestinal stem cells (ISCs) and differentiation of their progeny into various cell types, including enterocytes (ECs) that both mediate nutrient absorption and provide a barrier against pathogens. The signals that regulate transition of proliferative ISCs into differentiated ECs are not fully understood. IRBIT is an evolutionarily conserved protein that regulates ribonucleotide reductase (RNR), an enzyme critical for the generation of DNA precursors. Here, we show that IRBIT expression in ISC progeny within the Drosophila midgut epithelium cells is essential for their differentiation via suppression of RNR activity. Disruption of this IRBIT-RNR regulatory circuit causes a rapid, premature loss of intestinal tissue integrity as flies age. This age-related dysplasia can be reversed by suppression of RNR activity in ISC progeny. Collectively, our findings demonstrate an unexpected and novel role of the IRBIT-RNR pathway in gut homeostasis.

developmental biology↗