Intrinsically disordered arginine-glycine repeat domains tune sub-nucleolar compartmentalization in Caenorhabditis elegans.

Intrinsically disordered arginine-glycine (RG) repeat domains are enriched in multilayered biomolecular condensates such as the nucleolus. Caenorhabditis elegans nucleolar RG repeats are dispensable for nucleolar accumulation and instead contribute to the organization of sub-nucleolar compartments. The sufficiency of RG repeats to facilitate sub-nucleolar compartmentalization is unclear.

nucleolar RG repeats are sufficient for nucleolar accumulation but insufficient for sub-nucleolar compartmentalization.

Intrinsically disordered arginine-glycine (RG) repeat domains are enriched in multilayered biomolecular condensates such as the nucleolus. nucleolar RG repeats are dispensable for nucleolar accumulation and instead contribute to the organization of sub-nucleolar compartments. The sufficiency of RG repeats to facilitate sub-nucleolar compartmentalization is unclear.

A role for BYN-1/bystin in cellular uptake and clearance of residual bodies in the Caenorhabditis elegans germline.

GLH/Vasa/DDX4 helicases are core germ-granule proteins that promote germline development and fertility. A yeast-two-hybrid screen using Caenorhabditis elegans GLH-1 as bait identified BYN-1, the homolog of human bystin/BYSL. In humans, bystin promotes cell adhesion and invasion in gliomas, and, with its binding partner trophinin, triggers embryonic implantation into the uterine wall.

RG/RGG repeats in the C. elegans homologs of Nucleolin and GAR1 contribute to sub-nucleolar phase separation.

The intrinsically disordered RG/RGG repeat domain is found in several nucleolar and P-granule proteins, but how it influences their phase separation into biomolecular condensates is unclear. We survey all RG/RGG repeats in C. elegans and uncover nucleolar and P-granule-specific RG/RGG motifs.

NCAM1 and GDF15 are biomarkers of Charcot-Marie-Tooth disease in patients and mice.

Molecular markers scalable for clinical use are critical for the development of effective treatments and the design of clinical trials. Here, we identify proteins in sera of patients and mouse models with Charcot-Marie-Tooth disease (CMT) with characteristics that make them suitable as biomarkers in clinical practice and therapeutic trials. We collected serum from mouse models of CMT1A (C61 het), CMT2D (GarsC201R, GarsP278KY), CMT1X (Gjb1-null), CMT2L (Hspb8K141N) and from CMT patients with genotypes including CMT1A (PMP22d), CMT2D (GARS), CMT2N (AARS) and other rare genetic forms of CMT.

tRNA overexpression rescues peripheral neuropathy caused by mutations in tRNA synthetase.

Heterozygous mutations in six transfer RNA (tRNA) synthetase genes cause Charcot-Marie-Tooth (CMT) peripheral neuropathy. CMT mutant tRNA synthetases inhibit protein synthesis by an unknown mechanism. We found that CMT mutant glycyl-tRNA synthetases bound tRNA but failed to release it, resulting in tRNA sequestration.

Allele-specific RNA interference prevents neuropathy in Charcot-Marie-Tooth disease type 2D mouse models.

Gene therapy approaches are being deployed to treat recessive genetic disorders by restoring the expression of mutated genes. However, the feasibility of these approaches for dominantly inherited diseases - where treatment may require reduction in the expression of a toxic mutant protein resulting from a gain-of-function allele - is unclear. Here we show the efficacy of allele-specific RNAi as a potential therapy for Charcot-Marie-Tooth disease type 2D (CMT2D), caused by dominant mutations in glycyl-tRNA synthetase (GARS).

Accumulating Evidence for Axonal Translation in Neuronal Homeostasis.

The specialized structure of the neuron requires that homeostasis is sustained over the meter or more that may separate a cell body from its axonal terminus. Given this impressive distance and an axonal volume that is many times that of the cell body, how is such a compartment grown during development, re-grown after injury, and maintained throughout adulthood? While early answers to these questions focused on the local environment or the cell soma as supplying the needs of the axon, it is now well-established that the axon has some unique needs that can only be met from within. Decades of research have revealed local translation as an indispensable mechanism of axonal homeostasis during development and regeneration in both invertebrates and vertebrates.

Severity of Demyelinating and Axonal Neuropathy Mouse Models Is Modified by Genes Affecting Structure and Function of Peripheral Nodes.

Charcot-Marie-Tooth (CMT) disease is a clinically and genetically heterogeneous group of inherited polyneuropathies. Mutations in 80 genetic loci can cause forms of CMT, resulting in demyelination and axonal dysfunction. The clinical presentation, including sensory deficits, distal muscle weakness, and atrophy, can vary greatly in severity and progression.

Trk receptor signaling and sensory neuron fate are perturbed in human neuropathy caused by mutations.

Charcot-Marie-Tooth disease type 2D (CMT2D) is a peripheral nerve disorder caused by dominant, toxic, gain-of-function mutations in the widely expressed, housekeeping gene, The mechanisms underlying selective nerve pathology in CMT2D remain unresolved, as does the cause of the mild-to-moderate sensory involvement that distinguishes CMT2D from the allelic disorder distal spinal muscular atrophy type V. To elucidate the mechanism responsible for the underlying afferent nerve pathology, we examined the sensory nervous system of CMT2D mice. We show that the equilibrium between functional subtypes of sensory neuron in dorsal root ganglia is distorted by mutations, leading to sensory defects in peripheral tissues and correlating with overall disease severity.

Paclitaxel-induced epithelial damage and ectopic MMP-13 expression promotes neurotoxicity in zebrafish.

Paclitaxel is a microtubule-stabilizing chemotherapeutic agent that is widely used in cancer treatment and in a number of curative and palliative regimens. Despite its beneficial effects on cancer, paclitaxel also damages healthy tissues, most prominently the peripheral sensory nervous system. The mechanisms leading to paclitaxel-induced peripheral neuropathy remain elusive, and therapies that prevent or alleviate this condition are not available.

Synaptic Deficits at Neuromuscular Junctions in Two Mouse Models of Charcot-Marie-Tooth Type 2d.

Unlabelled: Patients with Charcot-Marie-Tooth Type 2D (CMT2D), caused by dominant mutations in Glycl tRNA synthetase (GARS), present with progressive weakness, consistently in the hands, but often in the feet also. Electromyography shows denervation, and patients often report that early symptoms include cramps brought on by cold or exertion. Based on reported clinical observations, and studies of mouse models of CMT2D, we sought to determine whether weakened synaptic transmission at the neuromuscular junction (NMJ) is an aspect of CMT2D.