Gain-of-function mutations in the housekeeping gene GARS1, which lead to the expression of toxic versions of glycyl-tRNA synthetase (GlyRS), cause the selective motor and sensory pathology characterizing Charcot-Marie-Tooth disease (CMT). Aberrant interactions between GlyRS mutants and different proteins, including neurotrophin receptor tropomyosin receptor kinase receptor B (TrkB), underlie CMT type 2D (CMT2D); however, our pathomechanistic understanding of this untreatable peripheral neuropathy remains incomplete. Through intravital imaging of the sciatic nerve, we show that CMT2D mice displayed early and persistent disturbances in axonal transport of neurotrophin-containing signaling endosomes in vivo.
View Article and Find Full Text PDFRegeneration of the neuromuscular junction (NMJ) leverages on extensive exchange of factors released from motor axon terminals (MATs), muscle fibers and perisynaptic Schwann cells (PSCs), among which hydrogen peroxide (HO) is a major pro-regenerative signal. To identify critical determinants of NMJ remodeling in response to injury, we performed temporal transcriptional profiling of NMJs from 2 month-old mice during MAT degeneration/regeneration, and cross-referenced the differentially expressed genes with those elicited by HO in SCs. We identified an enrichment in extracellular matrix (ECM) transcripts, including Connective Tissue Growth Factor (Ctgf), which is usually expressed during development.
View Article and Find Full Text PDFActa Neuropathol Commun
August 2022
Axonal transport ensures long-range delivery of essential cargoes between proximal and distal compartments, and is needed for neuronal development, function, and survival. Deficits in axonal transport have been detected at pre-symptomatic stages in the SOD1 and TDP-43 mouse models of amyotrophic lateral sclerosis (ALS), suggesting that impairments in this critical process are fundamental for disease pathogenesis. Strikingly, in ALS, fast motor neurons (FMNs) degenerate first whereas slow motor neurons (SMNs) are more resistant, and this is a currently unexplained phenomenon.
View Article and Find Full Text PDFDeficits in axonal transport are one of the earliest pathological outcomes in several models of amyotrophic lateral sclerosis (ALS), including SOD1 mice. Evidence suggests that rescuing these deficits prevents disease progression, stops denervation, and extends survival. Kinase inhibitors have been previously identified as transport enhancers, and are being investigated as potential therapies for ALS.
View Article and Find Full Text PDFAxonal transport maintains neuronal homeostasis by enabling the bidirectional trafficking of diverse organelles and cargoes. Disruptions in axonal transport have devastating consequences for individual neurons and their networks, and contribute to a plethora of neurological disorders. As many of these conditions involve both cell autonomous and non-autonomous mechanisms, and often display a spectrum of pathology across neuronal subtypes, methods to accurately identify and analyze neuronal subsets are imperative.
View Article and Find Full Text PDFFront Mol Neurosci
July 2020
Virus-mediated gene therapy has the potential to deliver exogenous genetic material into specific cell types to promote survival and counteract disease. This is particularly enticing for neuronal conditions, as the nervous system is renowned for its intransigence to therapeutic targeting. Administration of gene therapy viruses into skeletal muscle, where distal terminals of motor and sensory neurons reside, has been shown to result in extensive transduction of cells within the spinal cord, brainstem, and sensory ganglia.
View Article and Find Full Text PDFAxonal transport, which is the process mediating the active shuttling of a variety cargoes from one end of an axon to the other, is essential for the development, function, and survival of neurons. Impairments in this dynamic process are linked to diverse nervous system diseases and advanced ageing. It is thus essential that we quantitatively study the kinetics of axonal transport to gain an improved understanding of neuropathology as well as the molecular and cellular mechanisms regulating cargo trafficking.
View Article and Find Full Text PDFAmyotrophic lateral sclerosis (ALS) is a fatal, progressive neurodegenerative disease resulting from a complex interplay between genetics and environment. Impairments in axonal transport have been identified in several ALS models, but in vivo evidence remains limited, thus their pathogenetic importance remains to be fully resolved. We therefore analyzed the in vivo dynamics of retrogradely transported, neurotrophin-containing signaling endosomes in nerve axons of two ALS mouse models with mutations in the RNA processing genes TARDBP and FUS.
View Article and Find Full Text PDFAxonal transport is critical for neuronal homeostasis and relies on motor complexes bound to cargoes via specific adaptors. However, the mechanisms responsible for the spatiotemporal regulation of axonal transport are not completely understood. A recent study by Liao et al.
View Article and Find Full Text PDFSensitive and objective biomarkers of neuronal injury, degeneration, and regeneration can help facilitate translation of experimental findings into clinical testing. Whereas measures of upper motor neuron connectivity have been readily established, functional assessments of lower motor neuron (LMN) innervation of forelimb muscles are lacking. Compound muscle action potential (CMAP) and motor unit (MU) number estimation (MUNE) are well-established methods that allow longitudinal MU integrity monitoring in patients.
View Article and Find Full Text PDFNeurons are highly polarized cells that critically depend on long-range, bidirectional transport between the cell body and synapse for their function. This continual and highly coordinated trafficking process, which takes place via the axon, has fascinated researchers since the early 20th century. Ramon y Cajal first proposed the existence of axonal trafficking of biological material after observing that dissociation of the axon from the cell body led to neuronal degeneration.
View Article and Find Full Text PDFAxonal transport is the process whereby motor proteins actively navigate microtubules to deliver diverse cargoes, such as organelles, from one end of the axon to the other, and is widely regarded as essential for nerve development, function and survival. Mutations in genes encoding key components of the transport machinery, including motor proteins, motor adaptors and microtubules, have been discovered to cause neurological disease. Moreover, disruptions in axonal cargo trafficking have been extensively reported across a wide range of nervous system disorders.
View Article and Find Full Text PDFInhibition of histone deacetylase 6 (HDAC6) was shown to support axon growth on the nonpermissive substrates myelin-associated glycoprotein (MAG) and chondroitin sulfate proteoglycans (CSPGs). Though HDAC6 deacetylates α-tubulin, we find that another HDAC6 substrate contributes to this axon growth failure. HDAC6 is known to impact transport of mitochondria, and we show that mitochondria accumulate in distal axons after HDAC6 inhibition.
View Article and Find Full Text PDFFront Mol Neurosci
February 2018
Front Mol Neurosci
December 2017
Spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS) are severe nervous system diseases characterized by the degeneration of lower motor neurons. They share a number of additional pathological, cellular, and genetic parallels suggesting that mechanistic and clinical insights into one disorder may have value for the other. While there are currently no clinical ALS gene therapies, the splice-switching antisense oligonucleotide, nusinersen, was recently approved for SMA.
View Article and Find Full Text PDFTetanus (TeNT) and botulinum (BoNT) neurotoxins, the causative agents of tetanus and botulism, respectively, are the most potent toxic molecules known to mankind. This extreme potency is attributed to: i) their specificity for essential components of the neurotransmitter release machinery present at vertebrate synapses, and ii) their high-affinity targeting to motor neurons by binding to polysialogangliosides and protein receptors. Comprising the clostridial neurotoxin family, TeNT and BoNTs engage distinct surface receptors and intracellular sorting pathways in neurons.
View Article and Find Full Text PDFGene therapy can take advantage of the skeletal muscles/motor neurons anatomical relationship to restrict gene expression to the spinal cord ventral horn. Furthermore, recombinant adenoviruses are attractive viral-vectors as they permit spatial and temporal modulation of transgene expression. In the literature, however, several inconsistencies exist with regard to the intramuscular delivery parameters of adenoviruses.
View Article and Find Full Text PDFDiseases affecting the integrity of spinal cord motor neurons are amongst the most debilitating neurological conditions. Over the last decades, the development of several animal models of these neuromuscular disorders has provided the scientific community with different therapeutic scenarios aimed at delaying or reversing the progression of these conditions. By taking advantage of the retrograde machinery of neurons, one of these approaches has been to target skeletal muscles in order to shuttle therapeutic genes into corresponding spinal cord motor neurons.
View Article and Find Full Text PDFLower motor neuron dysfunction is one of the most debilitating motor conditions. In this regard, transgenic mouse models of various lower motor neuron dysfunctions provide insight into the mechanisms underlying these pathologies and can also aid the development of new therapies. Viral-mediated gene therapy can take advantage of the muscle-motor neuron topographical relationship to shuttle therapeutic genes into specific populations of motor neurons in these mouse models.
View Article and Find Full Text PDFSpinal cord injury damaging the rubrospinal tract (RST) interferes with skilled forelimb movement, but identification of the precise role of the RST in this behavior is impeded by the difficulty of surgically isolating the RST from other pathways running within the lateral funiculus (LF). The present study used a skilled reaching task and a behavioral/anatomical dissection method to identify the contribution of the RST to skilled forelimb movement. Rats were trained on the skilled reaching task and subjected to lesions of the LF.
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