The node of Ranvier influences thein vivoaxonal transport of mitochondria and signalling endosomes DOI Creative Commons
Andrew P. Tosolini, Federico Abatecola, Samuele Negro

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: June 5, 2024

Abstract Efficient long-range axonal transport is essential for maintaining neuronal function, and perturbations in this process underlie severe neurological diseases. We have previously demonstrated that signalling endosomes are transported vivo at comparable speeds across motor neurons (MNs) innervating different hindlimb muscles, as well between forelimb peripheral nerves. In contrast, faster MNs compared to sensory the same muscle. Found periodically myelin sheath, Nodes of Ranvier (NoR) short uncovered domains facilitate action potential propagation. Currently, it remains unresolved how distinct molecular structures NoR impact dynamics. Here, using intravital time-lapse microscopy sciatic nerves live, anaesthetised mice, we assessed diverse organelle dynamics NoR. first observed morphologies were similar fast slow MNs, found mitochondria accumulate on distal side both neuron subtypes. Assessment revealed a decrease velocity increase pausing organelles transit through NoR, followed by an speed adjacent intranodal region. Collectively, study has established two independent , relevance several pathologies affecting such neuropathy, diseases, and/or multiple sclerosis.

Language: Английский

Boosting BDNF in muscle rescues impaired axonal transport in a mouse model of DI-CMTC peripheral neuropathy DOI Creative Commons

Elena R. Rhymes,

Rebecca L. Simkin,

Qu Ji

et al.

Neurobiology of Disease, Journal Year: 2024, Volume and Issue: 195, P. 106501 - 106501

Published: April 6, 2024

Charcot-Marie-Tooth disease (CMT) is a genetic peripheral neuropathy caused by mutations in many functionally diverse genes. The aminoacyl-tRNA synthetase (ARS) enzymes, which transfer amino acids to partner tRNAs for protein synthesis, represent the largest family genetically linked CMT aetiology, suggesting pathomechanistic commonalities. Dominant intermediate type C (DI-CMTC) YARS1 driving toxic gain-of-function encoded tyrosyl-tRNA (TyrRS), mediated exposure of consensus neomorphic surfaces through conformational changes mutant protein. In this study, we first showed that human DI-CMTC-causing TyrRSE196K mis-interacts with extracellular domain BDNF receptor TrkB, an aberrant association have previously characterised several glycyl-tRNA synthetases 2D (CMT2D). We then performed temporal neuromuscular assessments YarsE196K mice modelling DI-CMT. determined homozygotes display selective, age-dependent impairment vivo axonal transport neurotrophin-containing signalling endosomes, phenocopying CMT2D mice. This replicated injection recombinant TyrRSE196K, but not TyrRSWT, into muscles wild-type Augmenting DI-CMTC muscles, or muscle-specific gene therapy, resulted complete correction. Therefore, work identifies non-cell autonomous pathomechanism common ARS-related neuropathies, and highlights potential boosting levels as therapeutic strategy.

Language: Английский

Citations

5
Processivity and BDNF-dependent modulation of signalling endosome axonal transport are impaired in aged mice DOI Creative Commons
David Villarroel‐Campos,

Elena R. Rhymes,

Andrew P. Tosolini

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 31, 2025

Abstract A healthy nervous system is reliant upon an efficient transport network to deliver essential cargoes throughout the extensive and polarised architecture of neurons. The trafficking cargoes, such as organelles proteins, particularly challenging within long projections neurons, which, in case axons, can be more than four orders magnitude longer cell bodies. It therefore unsurprising that disruptions axonal have been reported across neurological diseases. decline this process has also identified many aging models, perhaps compounding age-related neurodegeneration. Via intravital imaging, we recently determined that, despite a reduction overall motility, run speed displacement anterograde mitochondrial were unexpectedly enhanced aged mouse peripheral nerves. Here, determine how impacts different cargo, evaluated vivo signalling endosomes motor axons sciatic nerves from 3 22 months. Contrasting with mitochondria, did not detect alterations endosome speed, but found consistent rise pausing manifested after 18 We then treated muscles brain-derived neurotrophic factor (BDNF), which regulates neurons; however, observed no change processivity defect at months, downregulation BDNF receptor TrkB neuromuscular junction. Together, these findings indicate negatively likely through dampened neuron-muscle interface. Graphical

Language: Английский

Citations

0
Amyotrophic Lateral Sclerosis: Focus on Cytoplasmic Trafficking and Proteostasis DOI Creative Commons

Shrilaxmi Ms,

Saradindu Banerjee, Santosh R. D’Mello

et al.

Molecular Neurobiology, Journal Year: 2025, Volume and Issue: unknown

Published: April 3, 2025

Abstract Amyotrophic lateral sclerosis (ALS) is a progressive and fatal motor neuron disease characterized by the pathological loss of upper lower neurons. Whereas most ALS cases are caused combination environmental factors genetic susceptibility, in relatively small proportion cases, disorder results from mutations genes that inherited. Defects several different cellular mechanisms processes contribute to selective neurons (MNs) ALS. Prominent among these accumulation aggregates misfolded proteins or peptides which toxic These accumulating stress ability endoplasmic reticulum (ER) function normally, cause defects transport between ER Golgi, impair RNA, proteins, organelles, such as mitochondria, within axons dendrites, all degeneration MNs. Although dysfunction variety combines towards pathogenesis ALS, this review, we focus on recent advances concerning involvement defective stress, vesicular axonal transport. Graphical

Language: Английский

Citations

0
Hypertranscription: the invisible hand in stem cell biology DOI
Yun‐Kyo Kim, Évelyne Collignon,

S Bryn Martin

et al.

Trends in Genetics, Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 1, 2024

Language: Английский

Citations

3
The node of Ranvier influences the in vivo axonal transport of mitochondria and signalling endosomes DOI Creative Commons
Andrew P. Tosolini, Federico Abatecola, Samuele Negro

et al.

iScience, Journal Year: 2024, Volume and Issue: 27(11), P. 111158 - 111158

Published: Oct. 11, 2024

Language: Английский

Citations

3
Boosting BDNF in muscle rescues impaired axonal transport in a mouse model of DI-CMTC peripheral neuropathy DOI Creative Commons

Elena R. Rhymes,

Rebecca L. Simkin, Ji Qu

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: April 9, 2023

Abstract Charcot-Marie-Tooth disease (CMT) is a genetic peripheral neuropathy caused by mutations in many functionally diverse genes. The aminoacyl-tRNA synthetase (ARS) enzymes, which transfer amino acids to partner tRNAs for protein synthesis, represent the largest family genetically linked CMT aetiology, suggesting pathomechanistic commonalities. Dominant intermediate type C (DI-CMTC) YARS1 driving toxic gain-of-function encoded tyrosyl-tRNA (TyrRS), mediated exposure of consensus neomorphic surfaces through conformational changes mutant protein. In this study, we first showed that human DI-CMTC-causing TyrRS E196K mis-interacts with extracellular domain BDNF receptor TrkB, an aberrant association have previously characterised several glycyl-tRNA synthetases 2D (CMT2D). We then performed temporal neuromuscular assessments Yars mice modelling DI-CMT. determined homozygotes display selective, age-dependent impairment vivo axonal transport neurotrophin-containing signalling endosomes, phenocopying CMT2D mice. This replicated injection recombinant , but not WT into muscles wild-type Augmenting DI-CMTC muscles, or muscle-specific gene therapy, resulted complete correction. Therefore, work identifies non-cell autonomous pathomechanism common ARS-related neuropathies, and highlights potential boosting levels as therapeutic strategy.

Language: Английский

Citations

1
The node of Ranvier influences thein vivoaxonal transport of mitochondria and signalling endosomes DOI Creative Commons
Andrew P. Tosolini, Federico Abatecola, Samuele Negro

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: June 5, 2024

Abstract Efficient long-range axonal transport is essential for maintaining neuronal function, and perturbations in this process underlie severe neurological diseases. We have previously demonstrated that signalling endosomes are transported vivo at comparable speeds across motor neurons (MNs) innervating different hindlimb muscles, as well between forelimb peripheral nerves. In contrast, faster MNs compared to sensory the same muscle. Found periodically myelin sheath, Nodes of Ranvier (NoR) short uncovered domains facilitate action potential propagation. Currently, it remains unresolved how distinct molecular structures NoR impact dynamics. Here, using intravital time-lapse microscopy sciatic nerves live, anaesthetised mice, we assessed diverse organelle dynamics NoR. first observed morphologies were similar fast slow MNs, found mitochondria accumulate on distal side both neuron subtypes. Assessment revealed a decrease velocity increase pausing organelles transit through NoR, followed by an speed adjacent intranodal region. Collectively, study has established two independent , relevance several pathologies affecting such neuropathy, diseases, and/or multiple sclerosis.

Language: Английский

Citations

0