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At least 19 recordsLinked to original sources
PubMed2026

Heat shock protein 40 enhances axon regeneration in a mouse model of traumatic optic neuropathy.

Retinal ganglion cell death occurs following injury to the optic nerve either by trauma or in disease such as glaucoma, leading to severe vision loss. Recent innovations have demonstrated that optic nerve regeneration is feasible; however, the regeneration is limited. The aim of the present study is to identify genomic elements enhancing axon regeneration. We have taken a forward genetics approach using the BXD recombinant mouse strains to identify a gene that increases the extent of optic nerve regeneration. Axon regeneration was induced by knocking down Pten in retinal ganglion cells using adeno-associated virus to deliver an shRNA followed by an intravitreal injection of Zymosan with CPT-cAMP that produced a mild inflammatory response. Retinal ganglion cell axons were damaged by optic nerve crush. Following a 12-day survival period, regenerating axons were labeled by intravitreal injection of Cholera Toxin B conjugated with Alexa Fluor 647. Two days later, labeled axons within the optic nerve were examined to determine the number of regenerating axons and the distance they traveled down the optic nerve. The analysis revealed a surprising difference in the amount of axonal regeneration across all 33 BXD strains. There was a 7.5-fold difference in the number of regenerating axons and a 4-fold difference in the distance traveled by regenerating axons. These data were used to generate an interval map defining genomic loci that modulate enhanced axonal regeneration. A quantitative trait locus modulating axon regeneration was identified on Chromosome 14 (115 to 119 Mb). Within this locus were 16 annotated genes. Subsequent testing revealed that one candidate gene, Dnajc3, modulated axonal regeneration. Dnajc3 encodes heat shock protein 40 (HSP40), a molecular chaperone. Knocking down Dnajc3 in the high regenerative strain (BXD90) led to a decreased regeneration response, whereas, overexpression of Dnajc3 in a low regenerative strain (BXD34) resulted in an increased regeneration response. These findings reveal that Dnajc3 not only increases the number of regenerating axons, but also increases the distance that axons travel. The enhanced regeneration will prove to be critical for functional recovery in humans, where the distance axons travel to their targets is considerably longer than that of mice.

axon regeneration↗
PubMed1975

Constitution and properties of axonal membranes of crustacean nerves.

The purification of axonal membranes of crustaceans was followed by measuring enrichment in [3H]tetrodotoxin binding capacity and in Na+, K+-ATPase activity. A characteristic of these membranes is their high content of lipids and their low content of protein as compared to other types of plasmatic membranes. The axonal membrane contains myosin-like, actin-like, tropomyosin-like, and tubulin-like proteins. It also contains Na+, K+-ATPase and acetylcholinesterase. The molecular weights of these two enzymes after solubilization are 280,000 and 270,000, respectively. The molecular weights of the catalytic subunits are 96,000 for ATPase and 71,000 for acetylcholinesterase. We confirmed the presence of a nicotine binding component in the axonal membrane of the lobster but we have been unable to find [3H]nicotine binding to crab axonal membranes. The binding to axonal membranes og of the sodium channel, has been studied in detail. The dissociation constant for the binding of [3H]tetrodotoxin to the axonal membrane receptor is 2.9 nM at pH 7.4. The concentration of the tetrodotoxin receptor in crustacean membranes is about 10 pmol/mg of membrane protein, 7 times less than the acetylcholinesterase, 30 times less than the Na+, K+-ATPase, and 30 times less than the nicotine binding component in the lobster membrane. A reasonable estimate indicates that approximately only one peptide chain in 1000 constitutes the tetrodotoxin binding part of the sodium channel in the axonal membrane. Veratridine, which acts selectively on the resting sodium permeability, binds to the phospholipid part of the axonal membrane. [3H]Veratridine binding to membranes parallels the electrophysiological effect. Veratridine and tetrodotoxin have different receptor sites. Although tetrodotoxin can repolarize the excitable membrane of a giant axon depolarized by veratridine, veratridine does not affect the binding of [3H]tetrodotoxin to purified axonal membranes. Similarly, tetrodotoxin does not affect the binding of [3H]veratridine to axonal membranes. Scorpion neurotoxin I, a presynaptic toxin which affects both the Na+ and the K+ channels, does not interfere with the binding of [3H]tetrodotoxin or [3H]veratridine to axonal membranes. Tetrodotoxin, veratridine, and scorpion neurotoxin I, which have in common the perturbation of the normal functioning of the sodium channel, act upon three different types of receptor sites.

Acetylcholinesterase↗
PubMed2026

Domain-specific mutations in unc-6/Netrin differentially affect dorsal-ventral axon pathfinding in Caenorhabditis elegans.

UNC-6/Netrin is a conserved regulator of dorsal-ventral axon and cell migrations. Here, we identified missense mutations in distinct UNC-6 domains and assessed their roles in dorsal VD/DD motor axon guidance and ventral anterior ventral microtubule (AVM) axon guidance. A missense mutation in a conserved residue of the laminin N-terminal (LN) domain (G289D) resulted in dorsal and ventral axon guidance defects similar to the unc-6 null. A distinct missense mutation in the LN domain (S120F) strongly perturbed ventral AVM axon guidance with minimal effects on dorsal VD/DD axon guidance. Mutations altering cysteine residues involved in disulfide bonding in the epidermal growth factor (EGF) domains were analyzed. EGF1(C321G) and EGF2(C347Y) caused both ventral and dorsal axon guidance defects, whereas EGF3(C410Y) specifically disrupted dorsal axon guidance. The crystal structure of UNC-6 shows conserved N-linked glycosylation at N114 and N128. These sites were not solely required for axon guidance, but mutations interacted genetically with unc-40 and unc-5 mutations, indicating that these residues have a role in UNC-6 signaling. Our results reveal the effects of UNC-6 domains on dorsal-ventral axon guidance and will inform studies on how these distinct UNC-6 domains interact with guidance receptors (e.g. UNC-40/DCC and UNC-5) and other extracellular molecules to mediate dorsal-ventral axon guidance.

Animals↗
PubMed2026

[Laryngeal squamous cell carcinoma-derived exosomes promote neuronal axonal growth by remodeling the neural microenvironment].

Objective: Perineural invasion (PNI) is a critical determinant of poor prognosis in laryngeal squamous cell carcinoma (LSCC), but its underlying mechanisms remain unclear. This study aimed to investigate whether LSCC-derived exosomes induce axonal growth by delivering neuroactive molecules, thereby contributing to tumor perineural invasion. Methods: Clinical data from the laryngeal cancer cohort of The Cancer Genome Atlas Head and Neck Squamous Cell Carcinoma (TCGA-HNSC) dataset were analyzed. Propensity score matching (PSM) and Cox regression were used to evaluate the prognostic value of nerve density, and these findings were validated using 35 pairs of laryngeal cancer and adjacent normal tissue specimens collected at Yantai Yuhuangding Hospital between 2022 and 2026 to assess neural morphological changes. Exosomes were isolated from the human LSCC cell line AMC-HN-8, characterized by quality-control assays, and co-cultured with PC12 cells. A rescue experiment using GW4869, a specific inhibitor of neutral sphingomyelinase, was performed to confirm the exosome-dependent effect. Neurite outgrowth was evaluated by immunofluorescence, and the expression of axonal growth-related genes was measured by RT-qPCR. Targeted metabolomics was employed for the absolute quantification of neuroactive metabolites within the vesicles and for pathway enrichment analysis. Results: After PSM adjustment, high nerve density was identified as an independent poor prognostic factor in LSCC patients (HR=2.10, P=0.035), with particularly pronounced prognostic value in the early-stage node-negative (N0) subgroup (HR=4.07, P=0.001). Pathological sections showed high expression of the neural markers &#x3b2;III-tubulin and PGP9.5 in LSCC tissues (&#x3b2;III-tubulin: t=2.234, P<0.05; PGP9.5: t=2.575, P<0.05). Exosomes were successfully isolated from AMC-HN-8 cells and passed quality control. In vitro assays showed that LSCC-derived exosomes significantly promoted neurite extension and branching in PC12 cells (t=4.147, P<0.000 1) and upregulated core axonal growth genes, including GAP-43, NEFL, and NEFM (GAP-43: t=3.698, P<0.05; NEFL: t=5.113, P<0.01; NEFM: t=5.263, P<0.01); this effect was completely reversed by the exosome-release inhibitor GW4869 (t=3.535, P<0.001). Targeted metabolomics revealed a specific enrichment of 12 neurotransmitters and metabolites within LSCC exosomes, centered on glutamine (83.411 &#x3bc;mol/L, FC=1.88) and glutamate (18.461 &#x3bc;mol/L, FC=1.21), which were significantly enriched in signaling pathways such as "central carbon metabolism in cancer" and "glutamatergic synapse". Conclusion: Nerve density is a potential adverse prognostic factor in patients with LSCC. LSCC-derived exosomes can directly induce axonal growth in neuron-like cells, suggesting that tumor cells actively remodel the neural microenvironment and drive axonal growth through exosome-mediated long-range signaling.

Exosomes↗
PubMed1976

Separately developing axonal uptake of 5-hydroxytryptamine and norepinephrine in the fetal ileum of the rabbit.

Uptake of 5-hydroxytryptamine (5-HT) by adult and fetal rabbit's ileum was studied. The adult myenteric plexus accumulated tritium when incubated with tritiated 5-HT. However, in addition to labeled 5-HT, tritiated 5-hydroxyindole acetic acid and, when monoamine oxidase (MAO) was inhibited, 5-HT-o-glucuronide were found in the tissue. Two uptake processes differing in affinity could be defined. Only the high affinity process was saturable. Fetal ileum took up tritiated 5-HT but glucuronidation did not occur when MAO was inhibited. The uptake of tritiated 5-HT by the fetal ileum was due to a single, saturable, temperature sensitive (Q10 at 27-37 degress C = 2.4) process inhibited by ouabain. It was identical to the high affinity uptake found in adult tissue. This specific high affinity uptake could be found as early as the 16th day of gestation, 5-8 days before uptake of norepinephrine (NE) begins. Light and electron microscope radioautography revealed that the uptake of 5-HT was primarily into axons and a characteristic structure called the expanded process, both in the myenteric plexus. Both contained dense-cored vesicles. Axons were not labeled by tritiated NE until after 24 days and the expanded process was never labeled by tritiated NE. This study shows that uptake of 5-HT is a property of distinct system of axons in the mammalian myenteric plexus which develops prior to adrenergic axons during ontogeny.

Animals↗
PubMed1976

Different types of synaptic vesicles in axons of the retractor penis muscle of the bull.

Three types of axon profiles were observed in the smooth muscle of the retractor penis and the penile artery of the bull: 1. profiles containing small granular vesicles, presumably representing adrenergic axons; 2. profiles containing small agranular vesicles, presumably representing cholinergic axons; 3. profiles containing numerous large and small granular vesicles. The third type of profile was not found in the vas deferens or the metatarsal artery. It is therefore possible that this type of profile represents the non-adrenergic, non-cholinergic inhibitory nerves, the presence of which has previously been pharmacologically indicated in these tissues.

Animals↗
PubMed2025

Axonal injury is a targetable driver of glioblastoma progression.

Glioblastoma (GBM) is an aggressive and highly therapy-resistant brain tumour1,2. Although advanced disease has been intensely investigated, the mechanisms that underpin the earlier, likely more tractable, stages of GBM development remain poorly understood. Here we identify axonal injury as a key driver of GBM progression, which we find is induced in white matter by early tumour cells preferentially expanding in this region. Mechanistically, axonal injury promotes gliomagenesis by triggering Wallerian degeneration, a targetable active programme of axonal death3, which we show increases neuroinflammation and tumour proliferation. Inactivation of SARM1, the key enzyme activated in response to injury that mediates Wallerian degeneration4, was sufficient to break this tumour-promoting feedforward loop, leading to the development of less advanced terminal tumours and prolonged survival in mice. Thus, targeting the tumour-induced injury microenvironment may supress progression from latent to advanced disease, thereby providing a potential strategy for GBM interception and control.

Glioblastoma↗
PubMed2024

Dominant NARS1 mutations causing axonal Charcot-Marie-Tooth disease expand NARS1-associated diseases.

Pathogenic variants in six aminoacyl-tRNA synthetase (ARS) genes are implicated in neurological disorders, most notably inherited peripheral neuropathies. ARSs are enzymes that charge tRNA molecules with cognate amino acids. Pathogenic variants in asparaginyl-tRNA synthetase (NARS1) cause a neurological phenotype combining developmental delay, ataxia and demyelinating peripheral neuropathy. NARS1 has not yet been linked to axonal Charcot-Marie-Tooth disease. Exome sequencing of patients with inherited peripheral neuropathies revealed three previously unreported heterozygous NARS1 variants in three families. Clinical and electrophysiological details were assessed. We further characterized all three variants in a yeast complementation model and used a knock-in mouse model to study variant p.Ser461Phe. All three variants (p.Met236del, p.Cys342Tyr and p.Ser461Phe) co-segregate with the sensorimotor axonal neuropathy phenotype. Yeast complementation assays show that none of the three NARS1 variants support wild-type yeast growth when tested in isolation (i.e. in the absence of a wild-type copy of NARS1), consistent with a loss-of-function effect. Similarly, the homozygous knock-in mouse model (p.Ser461Phe/Ser472Phe in mouse) also demonstrated loss-of-function characteristics. We present three previously unreported NARS1 variants segregating with a sensorimotor neuropathy phenotype in three families. Functional studies in yeast and mouse support variant pathogenicity. Thus, NARS1 is the seventh ARS implicated in dominant axonal Charcot-Marie-Tooth disease, further stressing that all dimeric ARSs should be evaluated for Charcot-Marie-Tooth disease.

Charcot&#x2013;Marie&#x2013;Tooth disease↗
PubMed1976

Mechanism of action of quinidine on squid axon membranes.

The mechanism of action of quinidine on squid axons has been examined by means of voltage clamp and internal perfusion techniques. When applied either externally or internally, quinidine HCl suppresses both sodium and potassium conductance increases, the effect on the former accounting for the observed decrease in action potential. The potassium conductance in quinidine undergoes a marked inactivation in a manner dependent upon the membrane potential and time, accounting for the observed prolongation of the terminal falling phase of the action potential. Quinidine methiodide exhibits the effect similar to that of quinidine HCl only when applied internally. The dissociation constants of quinidine in suppressing the sodium conducting system are estimated to be 2.4 x 10(-4) and 4.0 x 10(-4) M for quinidine HCl and methiodide, respectively. The dissociation constant of quinidine in suppressing the potassium-conducting system decreases with increasing step depolarization. When applied externally to the intact axons, quinidine HCl is more effective at external pH 8.6 than at 7.3. When perfused internally, quinidine HCl is more effective at internal pH 7.0 than at 8.0, and the potency is related to the calculated internal concentration of the charged form rather than that of the uncharged form. These results lead to the conclusion that quinidine HCl penetrates the nerve membrane in the uncharged form, is ionized in the axon and blocks the sodium and potassium conductances primarily in the charged form. Thus, quinidine and local anesthetics share some features in the terms of the site of action and active form.

Action Potentials↗
PubMed1976

Intracellular pH transients in squid giant axons caused by CO2, NH3, and metabolic inhibitors.

The intracellular pH (pHi) of squid giant axons has been measured using glass pH microelectrodes. Resting pHi in artificial seawater (ASW) (pH 7.6-7.8) at 23 degrees C was 7.32 +/- 0.02 (7.28 if corrected for liquid junction potential). Exposure of the axon to 5% CO2 at constant external pH caused a sharp decrease in pHi, while the subsequent removal of the gas caused pHi to overshoot its initial value. If the exposure to CO2 was prolonged, two additional effects were noted: (a) during the exposure, the rapid initial fall in pHi was followed by a slow rise, and (b) after the exposure, the overshoot was greatly exaggerated. Application of external NH4Cl caused pHi to rise sharply; return to normal ASW caused pHi to return to a value below its initial one. If the exposure to NH4Cl was prolonged, two additional effects were noted: (a) during the exposure, the rapid initial rise in pHi was followed by a slow fall, and (b) after the exposure, the undershoot was greatly exaggerated. Exposure to several weak acid metabolic inhibitors caused a fall in pHi whose reversibility depended upon length of exposure. Inverting the electrochemical gradient for H+ with 100 mM K-ASW had no effect on pHi changes resulting from short-term exposure to azide. A mathematical model explains the pHi changes caused by NH4Cl on the basis of passive movements of both NH3 and NH4+. The simultaneous passive movements of CO2 and HCO3-cannot explain the results of the CO2 experiments; these data require the postulation of an active proton extrusion and/or sequestration mechanism.

Ammonium Chloride↗
PubMed2026

RFC1 Repeat Expansions in Chronic Idiopathic Axonal Polyneuropathy: Prevalence, Phenotype, and Diagnostic Implications.

BACKGROUND AND AIMS: Chronic idiopathic axonal polyneuropathy (CIAP) accounts for approximately 20%-30% of adult-onset axonal polyneuropathies. Pathogenic RFC1 repeat expansions have emerged as a frequent cause of idiopathic sensory neuropathy, but their recognition in routine clinical practice may be challenging, particularly in the presence of potentially confounding comorbidities. We aimed to determine the prevalence of pathogenic RFC1 repeat expansions in a well-defined CIAP cohort, characterize the associated clinical and electrophysiological phenotype, and evaluate whether coexisting well-controlled diabetes mellitus (DM) or monoclonal gammopathy of undetermined significance (MGUS) may hinder recognition of RFC1-related neuropathy. METHODS: We performed a retrospective observational study of adult patients with CIAP followed at a tertiary neuromuscular unit. All patients underwent RFC1 genetic testing. Clinical and electrophysiological features were compared between RFC1+ and RFC1- patients in the full cohort and after exclusion of patients with DM or MGUS. RESULTS: Ninety patients met CIAP criteria and were analyzed. Twenty-four (27%) carried biallelic pathogenic AAGGG repeat expansions in RFC1, of whom 6 (25%) had coexisting DM or MGUS. Compared with RFC1- patients, RFC1+ individuals more frequently exhibited dysautonomic symptoms, unsteadiness, history of falls, need for walking support, chronic cough, impaired vibration sense in the upper limbs and up to the knees in the lower limbs, brisk upper-limb reflexes, mild cerebellar signs, an abnormal head-impulse test, and a positive Romberg's test. Most of these differences persisted after exclusion of DM or MGUS. Electrophysiological studies in RFC1+ patients showed widespread sensory nerve involvement, including the upper limbs, with relative motor sparing, whereas RFC1- patients exhibited a more typical length-dependent pattern. INTERPRETATION: Biallelic AAGGG repeat expansions in RFC1 were identified in 27% of patients with CIAP. Specific clinical and electrophysiological features may help distinguish RFC1-related disease from other forms of CIAP and identify candidates for genetic testing, even in the presence of potentially confounding comorbidities such as well-controlled DM or MGUS.

Humans↗
PubMed1976

Aminopyridines and sparteine as inhibitors of membrane potassium conductance: effects on Myxicola giant axons and the lobster neuromuscular junction.

The effects of the compounds 2-, 3- and 4-aminopyridine and sparteine on membrane conductance changes were examined using both voltage-clamped Myxicola axons and the lobster neuromuscular junction. In Myxicola axons, the aminopyridines very specifically inhibited the potassium conductance when applied at concentrations of 0.1 mM to 5 mM without any apparent effect of resting membrane potential. Concentrations in excess of 5 mM were needed to inhibit noticeably the sodium conductance. Potassium conductance-voltage curves were shifted in the depolarized direction along the voltage axis with no significant change in shape. There were only minor changes in the kinetics of potassium activation. In high potassium solutions, both inward and outward potassium currents were equally sensitive to the aminopyridines. Sparteine was, in general, found to be a more potent, but somewhat less specific, inhibitor of the potassium conductance. In contrast to the aminopyridines, sparteine was more effective when applied at basic pH and in addition tended to produce a noticeable degree of potassium inactivation. When applied to the lobster neuromuscular junction, 2-aminopyridine and sparteine dramatically increased the amplitude of both excitatory and inhibitory postjunctional potentials, with little or no change in resting potential, resting input conductance, reversal potential, or miniature end plate potential amplitude or frequency. Quantal content per fiber was increased by approximately a factor of 3 for the excitatory responses.

Animals↗
PubMed2025

Multi-omic phenotyping of iPSC-derived neurons harboring the MAPT V337M mutation reveals tau hypophosphorylation and perturbed axon morphology pathways.

Tau aggregation is a hallmark of several neurodegenerative diseases, including Alzheimer's disease and frontotemporal dementia. There are disease-causing variants of the tau-encoding gene, MAPT, and the presence of tau aggregates is highly correlated with disease progression. However, the molecular mechanisms linking pathological tau to neuronal dysfunction are not well understood. This is in part due to an incomplete understanding of the normal functions of tau in development and aging, and how the associated molecular and cellular processes change in the context of causal disease variants of tau. To address these questions in an unbiased manner, we conducted multi-omic characterization of iPSC-derived neurons harboring the MAPT V337M mutation or MAPT knockdown. RNA-seq and phosphoproteomics revealed that both V337M mutation and tau knockdown perturbed levels of transcripts and phosphorylation of proteins related to axonogenesis or axon morphology. Surprisingly, we found that neurons with V337M tau had much lower tau phosphorylation than neurons with WT tau. Functional genomics screens uncovered regulators of tau phosphorylation in neurons and found that factors involved in axonogenesis modified tau phosphorylation in both MAPT WT and MAPT V337M neurons. Intriguingly, the p38 MAPK pathway specifically modified tau phosphorylation in MAPT V337M neurons. We propose that V337M tau perturbs tau phosphorylation and axon morphology pathways that are relevant to the normal function of tau, which could contribute to previously reported cognitive changes in preclinical MAPT variant carriers.

Journal Article↗
PubMed2025

FTO promotes weight gain via altering Kif1a splicing and axonal vesicle trafficking in AgRP neurons.

N6-methyladenosine (m6A) is an abundant chemical RNA modification involved in the regulation of many biological processes. The m6A demethylase FTO (fat mass and obesity-associated protein) is known to affect body weight, but its systemic context and underlying mechanisms remain unclear. Here, we found that mice lacking or overexpressing Fto in agouti-related peptide-expressing (AgRP) neurons in the hypothalamus exhibited decreased and increased body weight, respectively. FTO demethylated m6A on mRNAs for proteins associated with membrane trafficking and alternative splicing in AgRP neurons. Downstream, FTO-modulated alternative splicing of the axonal motor protein Kif1a affected its hinge region, which is relevant to the structure and function of KIF1A. Notably, Kif1a knockdown in AgRP neurons suppressed the weight gain of mice overexpressing Fto. In addition, FTO increased the trafficking and secretion of dense-core vesicles containing neuropeptides NPY and AgRP from AgRP neurons. Collectively, these results reveal a novel regulatory FTO-KIF1A axis in the brain affecting appetite-stimulating AgRP neurons and systemic energy homeostasis, via FTO regulation of the epitranscriptome of AgRP neurons.

Animals↗
PubMed1976

Effects of calcium on the local anesthetic suppression of ionic conductances in squid axon membranes.

The effects of varying the external calcium concentration on the suppression of membrane ionic conductances by procaine and benzocaine have been examined under voltage-clamped conditions. The suppression of peak conductance and steady-state conductance by procaine or benzocaine applied externally or internally was not affected by changing the external calcium concentration between 10 and 100 mM. When the calcium concentration was lowered below 10 mM (5 or 2 mM), the procaine effect was slightly potentiated. This augmentation could not be ascribed to an acceleration in the rate of penetration of procaine into the axon in low calcium solutions. The resting membrane conductance was slightly decreased by procaine in a manner independent of the external calcium concentration. The maximum effect of procaine on resting conductances was obtained at a concentration much lower than that required for maximum suppression of peak and steady-state conductances. The present results are not compatible with the hypothesis that calcium competes with local anesthetics for a negatively charged site on the membrane. It is suggested that hydrophobic interactions of local anesthetic molecules with the membrane affect the resting membrane conductance whereas coulombic interactions are responsible for the conductance changes observed during nerve activity.

Anesthetics, Local↗